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Effects of flavorings in electronic cigarettes on the use and appeal of e-cigarettes among youth and adults

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Effects of flavorings in electronic cigarettes on the use and appeal of e-cigarettes among youth and adults

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Content Running head: EFFECTS OF FLAVORINGS IN ELECTRONIC CIGARETTES

EFFECTS OF FLAVORINGS IN ELECTRONIC CIGARETTES ON THE USE AND APPEAL
OF E-CIGARETTES AMONG YOUTH AND ADULTS

by

Nicholas I. Goldenson

________________________________________________________________________

A Dissertation Presented to the

FACULTY OF THE USC GRADUATE SCHOOL

UNIVERSITY OF SOUTHERN CALIFORNIA

In Partial Fulfillment of the Requirements For

the Degree

DOCTOR OF PHILOSOPHY

Institute for Health Promotion and Disease Prevention Research

Keck School of Medicine

Department of Preventive Medicine

University of Southern California

May, 2019

Copyright 2019 Nicholas Isaac Goldenson
I
DEDICATION

To my family for their unconditional love and support.

II
ACKNOWLEDGEMENTS

I would like to acknowledge my mentor and dissertation committee chair, Dr. Adam
Leventhal, as well as my entire dissertation committee for their guidance and support. I want to
thank the entire USC Health, Emotion, and Addiction Laboratory (HEAL) faculty and staff,
without your dedication and hard work the research composing this dissertation would not have
been possible. This dissertation was also supported by the USC Tobacco Center of Regulatory
Science (USC-TCORS) and National Cancer Institute (NCIP50CA180905; PIs: Samet/Pentz)
and the National Institute on Drug Abuse (NIDAF31DA043303; PI: Goldenson).

III
Table of Contents

DEDICATION I
ACKNOWLEDGEMENTS II
LIST OF TABLES V
LIST OF FIGURES VI
ABSTRACT VII
CHAPTER 1: INTRODUCTION 1
BACKGROUND AND SIGNIFICANCE 1
FDA Regulation of Tobacco Products: The Family Smoking Prevention and Tobacco
Control Act 3
FDA Regulation of e-Cigarettes: The Deeming Rule 4
Regulatory Challenge of Flavored e-Cigarettes 5
Risk Flavored e-Cigarettes Pose to Youth 8
Potential of Flavored E-Cigarettes to Aid in Tobacco Harm Reduction 11
Impact of Acute Nicotine Withdrawal Symptoms on Smoking 13
Potential of e-Cigarettes to Reduce Withdrawal Symptoms and Cigarette Smoking 13
Importance of Considering Gender Differences in the Effects of Flavored e-Cigarettes 15
OVERVIEW OF DISSERTATION STUDIES 17
CHAPTER 2: ASSOCIATIONS OF SWEET-FLAVORED E-CIGARETTE USE WITH
SUBSEQUENT VAPING AND SMOKING AMONG ADOLESCENTS 22
ABSTRACT 22
INTRODUCTION 24
METHODS 26
Participants 26
Ethics Statement 27
Measures 27
Data Analysis 30
RESULTS 31
Association of e-Cigarette Flavor and Persistent Past 6-Month and 30-Day Vaping 32
Association of Sweet-Flavored e-Cigarette Use and Subsequent Dual Use 33
Sweet-Flavored e-Cigarette Use × Gender Interaction 33
DISCUSSION 33
CONCLUSIONS 37
CHAPTER 3: EFFECTS OF SWEET-FLAVORED E-CIGARETTES ON SMOKING
REINSTATEMENT IN NICOTINE-DEPRIVED SMOKERS 44
ABSTRACT 44
INTRODUCTION 46
METHODS 49
Participants 49
Design 49
Procedure 50
Materials 51
Measures 52
Data Analysis 55
RESULTS 57
IV
Sample Characteristics 57
Effects of e-Cigarette Flavor on Subjective Vaping Effects 58
Effects of e-Cigarette Flavor on Motivation to Reinstate Smoking 58
Effects of e-Cigarette Flavor on Subjective Nicotine Withdrawal Symptoms 59
Mediation of Flavor Condition on Smoking Outcomes by Subjective Vaping Effects 59
DISCUSSION 60
Conclusions 64
CHAPTER 4: GENDER DIFFERENCES IN THE APPEAL AND SENSORY EFFECTS
OF FLAVORED E-CIGARETTES AMONG YOUNG ADULT VAPERS 71
ABSTRACT 71
INTRODUCTION 73
METHODS 75
Participants 75
Design 75
Procedure 76
Materials 76
Measures 77
Data Analysis 78
RESULTS 79
Sample Characteristics 79
Gender × Flavor Interactions 79
Gender × Nicotine and Gender × Voltage Interactions 81
DISCUSSION 81
Conclusions 85
CHAPTER 5: DISCUSSION AND CONCLUSIONS 91
IMPLICATIONS 96
FUTURE RESEARCH DIRECTIONS 106
CONCLUDING REMARKS 109

REFERENCES 110

V
LIST OF TABLES

Table 1. Sample Characteristics and Tobacco Product Use by Baseline e-Cigarette Flavor…... 38
Table 2. Sample Descriptive Characteristics and Tobacco Product Use Across Follow-Ups...... 39
Table 3. Association of e-Cigarette Flavor and Subsequent Tobacco Product Use across
Follow-Up………………………………………………..……………………………. 40
Table 4. Associations between Sweet-Flavored e-Cigarette Use and Single and Dual
Product Use…………………………………………………………..………………... 41
Table 5. Associations between Total Number of e-Cigarette Flavors Used and Tobacco Product
Use…………………………………………………………………………………….. 42
Table 6. Sample Descriptive and Smoking Characteristics…………………………...………... 65
Table 7. Vaping-Induced Satiation Effects by e-Cigarette Flavor Condition…………………... 66
Table 8. Mediation of the Effects of Flavor Condition (Sweet vs. Tobacco) on BST
Outcomes by Subjective Vaping Effects…………………..………………………….. 67
Table 9. Sample Descriptive Characteristics by Gender………………………………….......... 87
Table 10. Two-way and Three-way Interactions of Gender, Flavor and Nicotine...............…… 88

VI
LIST OF FIGURES

Figure 1. The Harmfulness Continuum of Tobacco Products ………………...………………… 8
Figure 2. Conceptual Model: Public Health Impact of Flavored e-Cigarettes…………………. 21
Figure 3. Participant Accrual and Analytic Sample Flow Diagram……………..……………... 43
Figure 4. Experimental Session Timeline………………………………………………….…… 68
Figure 5. Smoking Delay Task Outcomes by Flavor Condition…………………………………69
Figure 6. Effects of Flavor on Acute Subjective Vaping Effects………………………………. 70
Figure 7. Gender Differences in the Appeal of Flavored e-Cigarettes………………………..... 89
Figure 8. Gender Differences in the Attractive Sensory Effects of Flavored e-Cigarettes…...… 90

VII
ABSTRACT
The prevalence of electronic cigarette (e-cigarette) use (vaping) has increased among
U.S. youth and adults in recent years. There is concern that e-cigarettes are adversely affecting
the health of youth, as they deliver nicotine and other potentially harmful chemicals, and may
contribute to the initiation of combustible tobacco product use. However, since e-cigarettes do
not involve the combustion of tobacco, and contain fewer toxicants and carcinogens than
combustible cigarettes, they may also be a lower risk substitute and putative harm reduction
measure for adult combustible cigarette smokers. Unlike combustible cigarettes, e-cigarettes are
available in a wide variety of flavorings that are extremely popular among youth as well as a
portion of current and former adult smokers who vape. Flavored e-cigarettes pose a regulatory
challenge, as they could both harm and possibly benefit population health. Understanding the
public health impact of flavored e-cigarettes requires considering vulnerable subpopulations,
such as female vapers and smokers, who may be more sensitive than males to flavored tobacco
products but also have greater difficulty quitting smoking. This dissertation contributes novel
evidence that can inform the current public health and regulatory debates regarding flavored e-
cigarettes by examining: (1) whether use of sweet-flavored e-cigarettes is associated with
subsequent (i.e., continued) vaping among adolescents; (2) if the use of sweet-flavored e-
cigarettes decreases smoking reinstatement behavior and nicotine withdrawal symptoms among
adult smokers during tobacco abstinence; and (3) if the appeal and sensory effects of flavored e-
cigarettes differ among male and female young adult vapers. This dissertation found that: (1) use
of sweet-flavored e-cigarettes (vs. non-sweet) was significantly associated with persistent vaping
among youth e-cigarette users across a two-year period; (2) the controlled administration of a
sweet-flavored (vs. tobacco-flavored) e-cigarette significantly reduced motivation to reinstate
VIII
smoking but did not significantly reduce withdrawal symptoms among adult smokers; and (3)
there were gender differences in the appeal of flavored e-cigarettes among young adult vapers,
with women (vs. men) preferring menthol-flavored e-cigarettes. These results extend previous
research demonstrating that flavored e-cigarettes are appealing among adolescents, and suggest
that regulatory strategies that alter the availability of flavored e-cigarettes may reduce the
prevalence of e-cigarette use among youth. Sweet-flavored e-cigarettes (vs. tobacco-flavored)
may help smokers resist smoking reinstatement during periods of tobacco abstinence, although
more data is needed to determine the effects of flavored e-cigarettes on smoking reduction and
cessation. The effects of flavored e-cigarettes may also differ in distinct segments of the
population (e.g., men and women), which could contribute to health disparities. Flavored e-
cigarettes likely pose a risk to the health youth, while their potential to aid adult smokers in
tobacco harm reduction is less clear.
1
CHAPTER 1: INTRODUCTION

Background and Significance

Flavorings have traditionally been added to tobacco products to enhance their appeal by
masking the natural harshness of tobacco and aversive taste of nicotine (Carpenter, Wayne, &
Connolly, 2007; Cummings, Morley, Horan, Steger, & Leavell, 2002; Feirman, Lock, Cohen,
Holtgrave, & Li, 2015; Kostygina, Glantz, & Ling, 2014; Lewis & Wackowski, 2006). A 1972
report by the tobacco manufacturer Brown and Williamson reveals that sweet-flavored cigarettes
have long been used to attract youth, “It’s a well-known fact that teenagers like sweet products.
Honey might be considered, […] Apples connote goodness and freshness and we see many
possibilities for our youth oriented cigarette with this flavor” (Brown & Williamson Tobacco
Corporation, 1972). Decades of tobacco control research demonstrate that flavored combustible
tobacco products (e.g., cigarettes, cigarillos) adversely impact public health by
disproportionately promoting the initiation of tobacco product use among youth (Ambrose et al.,
2015; Carpenter et al., 2007; Carpenter, Wayne, Pauly, Koh, & Connolly, 2005; Corey,
Ambrose, Apelberg, & King, 2014; Brown & Williamson Tobacco Corporation, 1972; Feirman
et al., 2015; King, Tynan, Dube, & Arrazola, 2014; Kostygina et al., 2014; Lewis & Wackowski,
2006; Villanti et al., 2017; Wayne & Connolly, 2002).
To combat this threat to public health, the 2009 Family Smoking Prevention and Tobacco
Control Act (hereafter, “The Act”) provided the U.S. Food and Drug Administration (FDA) with
the authority to regulate the manufacturing, distribution, and marketing of tobacco products, and
banned combustible cigarettes and several other tobacco products (e.g., roll-your-own tobacco
and smokeless tobacco) with characterizing flavors (i.e., non-tobacco flavorings, tastes or smells
[e.g., candy, fruit, chocolate]) other than menthol (Carvajal, Clissold, & Shapiro, 2009). The
2
growing popularity of flavored electronic cigarettes (e-cigarettes) among youth and young adults
(Ambrose et al., 2015; Corey et al., 2014; M. Harrell et al., 2016; Villanti et al., 2017) has
refocused attention on the public health impact of emerging flavored tobacco products, such as e-
cigarettes (Samet, Pentz, & Unger, 2016), which are currently available in a wide variety of
flavors despite the prohibition of characterizing flavors in combustible cigarettes (Zhu et al.,
2014).
While e-cigarettes were not included in The Act of 2009, the FDA reserved the authority
to “deem” new tobacco products subject to its regulation. In its 2016 Deeming Rule, the FDA
expanded its regulatory jurisdiction to include e-cigarette devices and their components, but no
determination was made regarding the ongoing availability of flavored e-cigarettes (Food &
Drug Administration, 2016). However, the FDA did discuss the issue of flavored alternative
tobacco products in the Deeming Rule, stating its need to balance, “Concerns regarding flavored
tobacco products’ appeal to youth [against] emerging evidence that some adults may potentially
use certain flavored tobacco products to transition away from combusted tobacco use” (Food &
Drug Administration, 2016).
As stated in the Deeming Rule, the FDA is seeking to strike the appropriate balance
between protecting youth from addiction to nicotine and tobacco products while encouraging the
innovation of less harmful, satisfying tobacco products for adult smokers to replace combustible
cigarettes. Accordingly, the FDA’s Center for Tobacco Products (CTP) has requested data on
ingredients and constituents, such as flavorings, that impact e-cigarette product appeal and user
behavior (Backinger, Meissner, & Ashley, 2016). Research among youth and adults is needed to
inform evidence-based regulatory policies that consider the net impact of the flavored e-
cigarettes in the population as a whole, among both tobacco users and non-users.
3

FDA Regulation of Tobacco Products: The Family Smoking Prevention and Tobacco Control
Act
Prior to The Act, the FDA’s Center for Drug Evaluation Research (CDER) only approved
therapeutic and medicinal products for smoking cessation (e.g., nicotine replacement therapies
[NRTs]), and the FDA did not regulate tobacco products intended for recreational use. The Act
of 2009 allowed the FDA for the first time to regulate recreational products made or derived
from tobacco (e.g., combustible cigarettes, smokeless tobacco), and established the Center for
Tobacco Products (CTP) to lead these efforts. The FDA primarily enacts the regulation of
tobacco products through two processes: (1) the establishment of product standards – the
requirement that tobacco products meet an appropriate standard for the protection of public
health; and (2) product review – the requirement that tobacco companies must notify the FDA
when they produce or market new or modified tobacco products (Husten & Deyton, 2013). As
such, the FDA can prohibit these tobacco products from being sold and distributed and require
changes in tobacco products in order to protect public health.
Product standards include the restriction or elimination of harmful constituents (e.g.,
ingredients and additives) from tobacco products as well as the evaluation of product appeal
(Husten & Deyton, 2013). Product review requires manufacturers to provide sufficient evidence
that a tobacco product does not adversely impact public health (e.g., contain toxins, increase
appeal) before they sell or modify a tobacco product. The FDA utilizes product review and
product standards in concert to regulate tobacco products, preventing tobacco manufacturers
from selling new products or making changes to existing products without informing the public.
Additionally, the FDA can enact product standards that discourage tobacco product use by
4
decreasing their addictiveness (e.g., reducing the nicotine concentration in combustible cigarettes
to non-addictive levels).

FDA Regulation of e-Cigarettes: The Deeming Rule
The FDA’s initial draft of the Deeming Rule banned flavorings in e-cigarettes and other
‘newly-deemed’ tobacco products (e.g., little cigars), but allowed manufacturers to apply for
marketing orders that would allow the sale of flavored products by providing scientific evidence
that a flavored product would benefit public health. However, the decision to ban these flavored
tobacco products was ultimately denied by the White House Office of Management and Budget,
and the text restricting the sale of flavored tobacco products was eliminated (i.e., red-lined) from
the Deeming Rule (Berman & Yang, 2016). In the final Deeming Rule (that did not include any
restriction of flavorings) e-cigarette manufacturers were allowed two years (until 2018) to
prepare and submit pre-market applications while newly-deemed products were allowed to
remain on the market essentially unregulated, and this deadline was recently extended until 2022.
As a result, there are currently no FDA product standards related to e-cigarettes, which has
contributed to their rapid proliferation across the marketplace in a wide variety of flavorings.
However, the FDA does intend to fully consider the issue of flavored tobacco products, and
recently issued an Advance Notice of Proposed Rulemaking (ANPRM) to obtain data and public
comments regarding the role flavors may play in: (1) the initiation of vaping among youth; and
(2) aiding adult combustible cigarette smokers in the reduction or cessation of smoking (Docket
No. FDA-2017-N-6565; 83 FR 12294-12301).

5
Regulatory Challenge of Flavored e-Cigarettes
The adverse health consequences of tobacco products are primarily caused by exposure to
the combustion of tobacco and its byproducts, with nicotine maintaining addiction to tobacco
(Abrams et al., 2018; Benowitz, 2009; Nutt et al., 2014). The Commissioner of the FDA and the
Director of CTP recognize this reality, stating in a 2017 editorial in the New England Journal of
Medicine, “Nicotine, though not benign, is not directly responsible for the tobacco-caused
cancer, lung disease and heart disease that kill hundreds of thousands of Americans each year”
(Gottlieb & Zeller, 2017). Hence, the FDA’s mission of promoting public health requires
considering the overall impact of different classes of tobacco products, some of which could
potentially harm youth but may also aid adult smokers in replacing combustible tobacco
products.
Harm reduction is an evidence-based public health strategy that aims to reduce the
adverse health consequences of drug use among individuals unwilling or unable to abstain from
use (Ritter, Ritter, Cameron, Ritter, & Cameron, 2006). Since e-cigarettes deliver nicotine via
non-combusted aerosols, they are widely believed to be less harmful than combustible cigarettes
(Goniewicz et al., 2017; Polosa et al., 2017). In the current marketplace, nicotine is delivered
through products that exist on a continuum of risk, with combustible cigarettes believed to be the
most harmful (see Figure 1) and e-cigarettes estimated by some experts (using currently
available data) to be closer in risk to other NRTs (Abrams et al., 2018; Nutt et al., 2014; Polosa,
Rodu, Caponnetto, Maglia, & Raciti, 2013). Tobacco harm reduction has been endorsed by the
Commissioner of the FDA and the Director of CTP, as they recognize the potential for
innovation to lead to less harmful products and are open to the possibility that e-cigarettes and
6
other noncombustible products may prove to be an effective component of tobacco control
policy in the 21
st
century (Gottlieb & Zeller, 2017).
In tobacco product assessment and regulatory science, appeal refers to the attractive and
rewarding characteristics of a product (e.g., taste, smell, appearance) that increase product liking
and encourage use (Henningfield, Hatsukami, Zeller, & Peters, 2011). Hence, the extent to
which a tobacco product is appealing is a key determinant of its likelihood to encourage
initiation and persistence of use among users. E-cigarette devices and their components
comprise a wide variety of products, with several modifiable product characteristics (e.g., flavor,
nicotine concentration) that appeal to youth (Camenga et al., 2018; Shang, Huang, Chaloupka, &
Emery, 2017; Zare, Nemati, & Zheng, 2018) as well as adult smokers (Farsalinos et al., 2013).
However, there is little data on the long-term effects of flavored e-cigarettes among nonsmoking
youth, and their ability to aid adult smokers in tobacco harm reduction is not well established
(Kalkhoran & Glantz, 2016; Khoudigian et al., 2016). Hence, it is currently unknown whether
the risk flavored e-cigarettes pose to youth exceeds or is balanced by their potential to aid adult
combustible cigarette smokers in tobacco harm reduction (Benowitz & Goniewicz, 2013).
One potential solution is a precision regulation framework that acknowledges individual
variability and bases regulatory decisions on specific e-cigarette product characteristics that may
differentially influence e-cigarette appeal and use in populations of interest (e.g., flavored e-
cigarettes may increase use among youth but not adults). Much in the same way that precision
medicine seeks to tailor treatments and prevention strategies to individual patient characteristics
(Ashley, 2015; Collins & Varmus, 2015), precision regulation can account for interindividual
differences in response to product characteristics when crafting regulatory policies for new and
rapidly evolving products. This novel paradigm, rather than a "one-size-fits-all-approach,"
7
would simultaneously balance the potential harms and benefits of flavored e-cigarettes in order
to optimally promote public health.
For example, if it was determined that a specific product characteristic (e.g., sweet-
flavoring) increased e-cigarette use among youth but did not encourage the substitution of e-
cigarettes for combustible cigarettes among adult smokers, it would follow that eliminating the
flavor would benefit public health. According to this paradigm, elucidating the net impact of
flavored e-cigarettes requires determining the impact of flavored e-cigarettes in two key
domains: (1) e-cigarette initiation, persistent e-cigarette use and transitions to combustible
tobacco products among youth; and (2) smoking reduction and cessation among adult
combustible cigarette smokers. Such data can inform evidence-based regulatory policies that
protect youth while also providing adult combustible tobacco users who need or want nicotine
with the opportunity to transition to less harmful products (Backinger et al., 2016; Food & Drug
Administration, 2016).
8
Figure 1. The Harmfulness Continuum of Tobacco Products

Note. Abbreviations: NRTs, nicotine replacement therapies. Tobacco products differ in their harmfulness and
toxicity, ranging from low harm (e.g., NRTs) to high harm (e.g., combustible cigarettes). Adapted from Abrams et
al., 2017 and Nutt et al., 2014.

Risk Flavored e-Cigarettes Pose to Youth
Research demonstrates that the initiation of tobacco products among youth is facilitated
by non-nicotine product characteristics, such as flavorings, that enhance appeal and improve the
sensory experience ( Carpenter et al., 2007; Feirman et al., 2015; Kostygina et al., 2014; Lewis &
Wackowski, 2006). The chemosensory science literature demonstrates that youth (vs. adults)
have a strong preference for sweet flavorings (Hoffman, Salgado, Dresler, Faller, & Bartlett,
2016) that activate neuropharmacological reward pathways in the brain (Touzani, Bodnar, &
0
10
20
30
40
50
60
70
80
90
100
Weighted Harm Scale
No Use NRTs / e-Cigarettes Smokeless Combusted Tobacco

No Harm Less Harmful Extreme Toxicity

9
Sclafani, 2010). Additionally, internal tobacco industry documents demonstrate that adolescents
are particularly susceptible to flavored tobacco products, and are often targeted by manufacturers
(Carpenter et al., 2007; Carpenter et al., 2005).
Youth frequently initiate vaping with flavored e-cigarettes (Ambrose et al., 2015; Corey
et al., 2014; Villanti et al., 2017), and the availability of appealing flavorings is a commonly
cited reason for experimentation with e-cigarettes by adolescents (Berg, 2015; Kong, Morean,
Cavallo, Camenga, & Krishnan-Sarin, 2014; Zhu et al., 2014). Recent data from national and
regional studies indicate that flavored e-cigarettes are used by the vast majority of adolescent
vapers (Harrell et al., 2016; Villanti et al., 2017)—in a study of Texas youth, over 95% of current
adolescent vapers reported currently using flavored e-cigarettes (Harrell et al., 2016). There is
also concern that the availability of flavored e-cigarettes may be attracting a new generation of
youth who would not otherwise use tobacco products (Kong & Krishnan-Sarin, 2017; Wills,
2017). Flavored e-cigarettes are perceived as less harmful than tobacco-flavored e-cigarettes
(Pepper, Ribisl, & Brewer, 2016), and youth who use e-cigarettes exhibit lower risk profiles
(e.g., fewer behavioral and mental health problems) than adolescents who smoke combustible
cigarettes (Leventhal et al., 2016; Wills, 2017; Wills, Knight, Williams, Pagano, & Sargent,
2015; Wills, Sargent, Gibbons, Pagano, & Schweitzer, 2016).
Controlled laboratory research (i.e., double-blind experiments) with vapers and smokers
demonstrate that sweet-flavored e-cigarettes are more rewarding than tobacco-flavored and
flavorless e-cigarettes (Audrain-McGovern, Strasser, & Wileyto, 2016; Goldenson et al., 2016;
Kim et al., 2016), with the sensory properties (i.e., sweetness, coolness) of flavored e-cigarettes
constituting a key element of their appeal (Goldenson et al., 2016; Kim et al., 2016). Qualitative
and experimental studies with vapers indicate that flavored e-cigarettes are also appealing
10
because they reduce the aversive (i.e., bitterness and harshness) qualities of nicotine (Rosbrook
& Green, 2016; Soule, Rosas, & Nasim, 2016). These results suggest that the endogenous
features of flavored e-cigarettes are inherently appealing to users, and may contribute to youth e-
cigarette initiation and continued use.
In addition to encouraging initiation (Harrell, Loukas, Jackson, Marti, & Perry, 2017;
Hong, Barrington-Trimis, Liu, Urman, & McConnell, 2017), flavored e-cigarettes may also
maintain persistent vaping among youth following initiation (Ambrose et al., 2015; Bold, Kong,
Cavallo, Camenga, & Krishnan-Sarin, 2016; Harrell et al., 2017; Tsai, 2018), increasing risk of
addiction to nicotine and exposure to aerosols that contain compounds of known and unknown
respiratory toxicity (Barrington-Trimis, Samet, & McConnell, 2014; Tierney, Karpinski, Brown,
Luo, & Pankow, 2015). In a cross-sectional study of Connecticut youth, preference for sweet-
flavored e-cigarettes was associated with increased past 30-day frequency of vaping (Morean et
al., 2018), and longitudinal data from this sample suggests that use of e-cigarettes due to the
presence of appealing flavorings is associated with continued e-cigarette use at a single 6-month
follow-up assessment (Bold et al., 2016). However, it is unknown if use of flavored e-cigarettes
increases risk of continued vaping over longer periods of time.
There is also concern that e-cigarettes may serve as a gateway to smoking, as a growing
body of research demonstrates that use of e-cigarettes is prospectively associated with
combustible cigarette initiation among nonsmoking youth (Barrington-Trimis et al., 2016;
Leventhal et al., 2015; Primack, Soneji, Stoolmiller, Fine, & Sargent, 2015; Soneji et al., 2017;
Wills et al., 2016). Additionally, cross-sectional data suggests that use of flavored e-cigarettes in
particular may be associated with combustible cigarette smoking. In two cross-sectional studies
use of flavored e-cigarettes was associated with: (1) increased susceptibility to combustible
11
cigarette smoking among nonsmoking youth (Chen et al., 2017); and (2) a reduced likelihood of
quitting smoking among adolescent combustible cigarette smokers (Dai & Hao, 2016). Thus,
flavored e-cigarettes may pose a distinct risk to adolescents due to their initial appeal, risk of
continued use and facilitation of transitions to combustible tobacco product use. Echoing these
concerns, the Deeming Rule states, “FDA understands that the appeal of flavors and use of
flavored tobacco products have an important role in the initiation and continued use of tobacco
products, [and] have determined that exercising enforcement discretion indefinitely could put
youth and young adults at risk for tobacco-related death and disease” (Food & Drug
Administration, 2016).

Potential of Flavored E-Cigarettes to Aid in Tobacco Harm Reduction
Smoking cigarettes remains the leading cause of preventable morbidity and mortality in
the United States (Health & Services, 2014). The majority of smokers report wanting to quit
smoking, as ceasing smoking significantly reduces the risk of smoking-related illnesses, yet even
the most intensive smoking cessation treatments demonstrate only modest rates of success—as
low as six percent according to recent estimates (Babb, 2017; Tobacco, 2008). Nicotine
replacement therapies (e.g., nicotine patch, gum and nasal spray) have existed in various forms
since the 1960’s, however, their long-term effectiveness at smoking cessation remains relatively
low among heavily nicotine-dependent smokers (Moore et al., 2009; Stead, Perera, Bullen, Mant,
& Lancaster, 2008), possibly as a result of slow nicotine delivery speed and the lack of stimuli
associated with smoking (Benowitz, 2009). E-cigarettes may offer a solution to these challenges,
as recent device models approach the nicotine delivery profile of combustible cigarettes (Hajek,
Przulj, Phillips, Anderson, & McRobbie, 2017) and replicate sensorimotor stimulation (e.g.,
12
hand-to-mouth gestures, stimulation of the airways) associated with smoking (Guillot,
Zvolensky, & Leventhal, 2015; Van Heel, Van Gucht, Vanbrabant, & Baeyens, 2017).
Nicotine is the primary psychoactive constituent of combustible cigarettes that maintains
tobacco dependence and smoking, but nicotine alone is considered minimally harmful to adults
(Hughes, 1994, 2007). The combustion of tobacco is the primary cause of tobacco-related
disease and death, as a leading tobacco control expert succinctly declared, “People smoke for
nicotine but they die from the tar” (Russell, 1976). The 2014 U.S. Surgeon General’s Report
(“The health consequences of smoking—50 years of progress”) emphasizes the importance of
eliminating use of combustible tobacco products specifically, stating, “The burden of death and
disease from tobacco use in the U.S. is overwhelmingly caused by cigarette and other combusted
tobacco products; rapid elimination of their use will dramatically reduce this burden” (Health &
Services, 2014).
Tobacco harm reduction involves decreasing the adverse health effects caused by
exposure to the combustion of tobacco, either by reducing the quantity of smoking or enabling
smokers to completely eliminate combustible tobacco product use. Accordingly, a number of
scientists and public health experts believe that the most important goal currently facing tobacco
control today is the reduction or elimination of combustible tobacco products by chronic users
(Benowitz, Donny, & Hatsukami, 2017). Researchers and public health entities, particularly in
Europe and the United Kingdom (McNeil et al., 2016; Physicians, 2016), believe that e-
cigarettes may offer a fruitful avenue for achieving this goal (Nutt et al., 2016; Polosa, Russell,
Nitzkin, & Farsalinos, 2017). However, it is important to note that the extant evidence from
clinical trials and observational studies is inconclusive regarding whether e-cigarettes can
13
effectively help smokers quit or reduce smoking (Bullen et al., 2010; Hartmann‐Boyce et al.,
2016; Kalkhoran & Glantz, 2016).

Impact of Acute Nicotine Withdrawal Symptoms on Smoking
Nicotine withdrawal symptoms emerge within hours following smoking abstinence as a
result of nicotine dependence, and include psychobiological manifestations such as irritability,
depression, increased hunger, concentration problems and cigarette craving (Hughes, 2007).
Withdrawal is most severe during acute stages of abstinence (Shiffman et al., 2006), and as a
result of withdrawal symptoms and accompanying distress smokers often relapse in the first 24
hours of cessation efforts (Brown, Herman, Ramsey, & Stout, 1998; Brown, Lejuez, Kahler, &
Strong, 2002; Hughes, 1992). The desire to suppress withdrawal symptoms has been shown to
mediate behavioral motivation to reinstate smoking (Aguirre, Madrid, & Leventhal, 2015)—
maintaining daily smoking and inhibiting cessation efforts among nicotine-dependent smokers
(Hughes, 1994, 2007). Thus, treating acute nicotine withdrawal among smokers is important for
several reasons: (1) withdrawal leads to clinically-significant distress that interferes with
functioning and quality of life; (2) withdrawal that emerges from short-term abstinence
contributes to the maintenance of daily smoking behavior; (3) the desire to suppress withdrawal
from longer periods of abstinence inhibits attempts to quit smoking and leads to relapse
following cessation.

Potential of e-Cigarettes to Reduce Withdrawal Symptoms and Cigarette Smoking
The alleviation of withdrawal symptoms may be an important reason that smokers who
are seeking to quit or reduce smoking adopt vaping. E-cigarette ever-use has increased in
14
prevalence among adult smokers in the past several years (Bao, Xu, Lu, Snetselaar, & Wallace,
2018; McMillen, Gottlieb, Shaefer, Winickoff, & Klein, 2015), with adult vapers reporting
smoking reduction or cessation as a common reason for e-cigarette use (Kalkhoran et al., 2017;
Richardson, Pearson, Xiao, Stalgaitis, & Vallone, 2014; Rutten et al., 2015). E-cigarettes deliver
pulmonary nicotine in bolus form, which allows for more efficient deliver compared to
traditional NRTs (West, 2006), and may enhance the pharmacological effects of nicotine and
reduce urges to smoke (Hajek et al., 2017). Laboratory evidence demonstrate that recent-
generation, high-power e-cigarettes can deliver nicotine to the bloodstream at levels approaching
combustible cigarettes (Hajek et al., 2017; Ramôa et al., 2015) and that e-cigarettes can reduce
acute nicotine withdrawal during tobacco abstinence (Dawkins, Kimber, Puwanesarasa, & Soar,
2015; Dawkins, Turner, Hasna, & Soar, 2012).
Evidence also indicates that use of e-cigarettes without nicotine can reduce acute
withdrawal symptoms (Przulj, McRobbie, & Hajek, 2016; Tseng et al., 2016; Van Heel et al.,
2017), suggesting that the non-nicotine (i.e., sensorimotor) properties of e-cigarettes may play a
role in suppressing withdrawal symptoms (Rose, 2006; Rose, Salley, Behm, Bates, & Westman,
2010). E-cigarettes are available in a wide variety of flavorings (Zhu et al., 2014), with vapers
reporting that flavor and sensory satisfaction are important reasons for vaping (Berg, 2015;
Farsalinos et al., 2013). Hence, determining if non-pharmacological e-cigarette product
characteristics, such as flavor, modulate the withdrawal-suppressive effects of e-cigarettes can
elucidate their ability to facilitate transitions away from combustible tobacco products.
The nicotine psychopharmacology, neuroscience and e-cigarette literatures suggest that
sweet-flavored e-cigarettes, compared to tobacco-flavored e-cigarettes, may be effective at
reducing nicotine withdrawal symptoms (Beauchamp, 2016; Hoffman et al., 2016). During
15
nicotine withdrawal, the administration of sweet-flavored chewing gum (vs. unflavored) has
been shown to reduce nicotine withdrawal symptoms (Cohen, Collins, & Britt, 1997; Cohen,
Collins, VanderVeen, & Weaver, 2010; Cortez-Garland, Cohen, VanderVeen, & Cook, 2010).
Additionally, laboratory evidence indicates that the administration of sweet-flavored e-cigarettes
(vs. non-sweet-flavored) enhances the acute appeal and reward of vaping among both e-cigarette
users and cigarette smokers (Audrain-McGovern et al., 2016; Goldenson et al., 2016; Kim et al.,
2016; Litt, Duffy, & Oncken, 2016). Furthermore, former smokers who have successfully
substituted e-cigarettes for combustible cigarettes cite flavor as a key factor in quitting smoking,
and state that restricting the availability of flavors would increase their craving for combustible
cigarettes (Barbeau, Burda, & Siegel, 2013; Farsalinos et al., 2013; Christopher Russell,
Dickson, & McKeganey, 2017). Hence, sweet-flavored e-cigarettes (vs. tobacco-flavored) may
be more effective at reducing smoking reinstatement behavior and nicotine withdrawal
symptoms in cigarette smokers seeking less-harmful alternatives to combustible cigarettes.

Importance of Considering Gender Differences in the Effects of Flavored e-Cigarettes
Understanding the public health impact of flavored e-cigarettes requires considering the
risks and benefits posed to the population as a whole, including vulnerable subpopulations. Prior
research has identified gender differences in reasons for smoking (e.g., women more frequently
smoke to control their weight and reduce stress) (Gritz, Nielsen, & Brooks, 1996), and suggests
that specific aspects of tobacco products may be differentially reinforcing. For example, female
combustible cigarette smokers (vs. male) are more strongly influenced by the non-
pharmacological sensory aspects of smoking (Perkins et al., 2001; Perkins, Jacobs, Sanders, &
Caggiula, 2002). Furthermore, tobacco industry documents reveal that manufacturers have long
16
been aware of gender differences in the sensory effects of combustible tobacco products, and
have designed products specifically to appeal to female smokers (Carpenter, Wayne, &
Connolly, 2005).
Female youth and young adults may be particularly vulnerable to flavored e-cigarettes, as
recent data suggest that the appeal and sensory effects of flavored e-cigarettes may vary by
gender (Oncken, Litt, McLaughlin, & Burki, 2015; Rosbrook & Green, 2016). An experiment
with menthol-flavored e-cigarettes found a three-way interaction between menthol, nicotine
content and gender, with females preferring menthol-flavored e-cigarettes, particularly in the
absence of nicotine (Rosbrook & Green, 2016). In a separate study of non-treatment seeking
smokers, female menthol smokers (vs. males) vaped less and rated e-cigarettes as less rewarding
when presented with a tobacco-flavored e-cigarette (Oncken, Litt, McLaughlin, & Burki, 2015).
Given females’ preference for the sensory aspects of smoking, flavored e-cigarettes that produce
sensations of sweetness, coolness and other desirable sensory effects may be particularly
appealing to female youth and may increase risk of initiating e-cigarette use and progressing to
regular use following initiation. Given that much of the extant research has compared menthol-
flavored e-cigarettes to tobacco-flavored e-cigarettes, data is needed to assess the appeal of
sweet-flavored e-cigarettes.
It is also important to consider that female (vs. male) smokers have greater difficulty
quitting and reducing smoking (Perkins, 2001; Perkins & Scott, 2008), and are at increased risk
of smoking-related illnesses (Prescott, Hippe, Schnohr, Hein, & Vestbo, 1998). Traditional
NRTs are less effective among female (vs. male) smokers, as female smokers have lower quit
rates and maintain fewer long-term treatment gains when using NRTs (Cepeda-Benito, Reynoso,
& Erath, 2004; Perkins & Scott, 2008). Preliminary evidence suggests that flavored e-cigarettes
17
(vs. tobacco-flavored) may help reduce smoking: in a smoking reduction trial cherry-flavored e-
cigarettes were rated as more appealing than tobacco-flavored e-cigarettes, and menthol-flavored
e-cigarettes (vs. tobacco) were more effective at reducing smoking over a 6-week follow-up
period (Litt et al., 2016). Thus, noncombustible nicotine delivery products that incorporate
appealing flavorings may offer a new harm reduction option for female smokers who have
difficulty quitting smoking with available NRTs (Perkins, 2001; Wetter et al., 1999).
Given the abovementioned evidence regarding gender differences in the effects of
tobacco products, the potential harms and benefits of flavored e-cigarettes may be amplified
among females. Determining if the appeal of flavored e-cigarettes differs among men and
women has important implications for two domains of public health discussed in this
dissertation: (1) the growing popularity of flavored e-cigarettes among youth; and (2) the
potential of e-cigarettes to aid adult combustible cigarette smokers in smoking reduction and
cessation. Such data can inform a precision regulation paradigm designed to prevent e-cigarette
use among vulnerable youth populations while also encouraging tobacco harm reduction among
adult treatment-resistant smokers.

Overview of Dissertation Studies
The primary goal of this dissertation is to examine the public health impact of flavored e-
cigarettes among youth vapers and adult smokers by integrating streams of laboratory and
observational data. In this dissertation the term ‘flavored e-cigarettes’ is used to refer to all non-
tobacco-flavored (or unflavored [flavorless]) e-cigarette products, including menthol, whereas
the term ‘sweet-flavored e-cigarettes’ refers to those labeled by the manufacturer with a
characterizing flavor considered sweet (e.g., candy, fruit), and does not include menthol
18
(Krüsemann, Boesveldt, de Graaf, & Talhout, 2018; Yingst, Veldheer, Hammett, Hrabovsky, &
Foulds, 2017). The three studies in this dissertation assess the appeal and use of flavored e-
cigarettes in three distinct populations: (1) adolescent high school e-cigarette users; (2) e-
cigarette-naïve adult daily smokers; and (3) young adult e-cigarette users. By determining the
impact of flavored e-cigarettes on: (1) persistent e-cigarette use and future combustible cigarette
use among youth; (2) smoking reinstatement behavior and nicotine withdrawal among adult
smokers; and (3) gender differences in the appeal and sensory characteristics of e-cigarettes
among young adult vapers, these studies will help elucidate the risks and benefits posed by
flavored e-cigarettes to the population as a whole.
The first study utilized a cohort of high school students to determine if the use of sweet-
flavored e-cigarettes (vs. non-sweet) by adolescent vapers was prospectively associated with
persistent e-cigarette and subsequent combustible cigarette use. The second study examined if
the controlled administration of e-cigarettes with sweet (vs. tobacco) flavorings suppressed
motivation to reinstate smoking and withdrawal symptoms among adult combustible cigarette
smokers who had never previously used e-cigarettes, and the third study assessed if the appeal of
flavored e-cigarettes differed between male and female young adult e-cigarette users in a
controlled laboratory setting.
A conference on the appeal of tobacco products recommended controlled human
laboratory research as a method of evaluating the appeal of novel tobacco products (Jack E
Henningfield et al., 2011). Accordingly, the two laboratory studies included in this dissertation
will utilize validated self-report and behavioral measures to assess the appeal and withdrawal-
suppressive effects of flavored e-cigarettes (Carter & Griffiths, 2009; Carter et al., 2009; J. E.
19
Henningfield, 2011). The within-subjects, double-blind, cross-over designs will reduce threats to
internal validity and isolate the effects of flavor.
This dissertation has several innovative features, and will contribute novel data to the
tobacco regulatory science and public health literatures. Longitudinal data regarding the effects
of flavored e-cigarettes among youth is sparse. While it is established that flavored e-cigarettes
are frequently used at e-cigarette initiation, it is unknown if flavored e-cigarette use is
prospectively associated with persistent vaping (following initial use) and future combustible
cigarette smoking. The majority of human laboratory research involving e-cigarettes has
primarily assessed the pharmacodynamics and pharmacokinetics of nicotine delivery, with less
research focusing on the effects of flavorings. The first laboratory study included in this
dissertation extends previous work on flavored e-cigarettes to include the effects of sweet-
flavored e-cigarettes on smoking reinstatement behavior and nicotine withdrawal among adult
smokers. The third study’s examination of gender differences in the appeal and sensory effects
of flavored e-cigarettes will extend the extant literature regarding females sensitivity to flavored
tobacco products, which may be particularly relevant for vaping. Additionally, this line of
research can provide a starting point for future work that can examine whether regulatory
restrictions are likely to increase or reduce tobacco-related health disparities among vulnerable
subpopulations. Together, the three studies will provide data that addresses questions of
scientific and regulatory significance.
This dissertation will utilize the methods of tobacco regulatory science to inform the
paradigm of precision regulation and addiction science. The data presented herein will elucidate
the public health impact of flavored e-cigarettes according to the FDA’s “population as a whole”
standard, among youth nonsmokers and adult smokers (see Figure 2). Future research can
20
extend the conceptual model regarding the effects of flavored e-cigarettes to specific product
characteristics and populations of interest.

21
Figure 2. Conceptual Model: Public Health Impact of Flavored e-Cigarettes

Note. Arrows (à) indicate predictive associations; red upward arrows represent population effects of flavored e-
cigarettes. The consequences of flavored e-cigarette use are displayed among two distinct populations: youth
nonsmokers and adult smokers.
E-Cigarette
Initiation
Substitution of
e-Cigarettes for
Combustible
Cigarettes
Regular Use
----------------------------------------------------------------------------------------
Youth Nonsmokers
Adult Smokers
Smoking
Reduction or
Cessation
Increased
Nicotine
Dependence
Transition to
Combustible
Tobacco Product
Use
Figure 1 | 6

Increased by
flavored
e-cigarettes

Maintained by
flavored
e-cigarettes
Effects of Flavored e-Cigarettes Consequences of Flavored e-Cigarettes
22
CHAPTER 2: ASSOCIATIONS OF SWEET-FLAVORED E-CIGARETTE USE WITH
SUBSEQUENT VAPING AND SMOKING AMONG ADOLESCENTS

ABSTRACT

BACKGROUND: Use of electronic cigarettes (e-cigarettes) has increased among U.S.
adolescents in recent years. Unlike combustible cigarettes, e-cigarettes are available in a wide
variety of sweet flavorings. There is concern that sweet-flavored e-cigarettes may pose a threat
to the public health of youth, as the vast majority of youth e-cigarette users initiate e-cigarette
use with flavored products. However, it is unknown if the use of sweet-flavored e-cigarettes is
prospectively associated with persistent use of e-cigarettes and subsequent combustible cigarette
smoking. METHODS: A cohort of 10
th
grade high school students participated in a longitudinal
survey across five semi-annual assessments from 2015-2017. Participants (N=564) reported all
the e-cigarette flavors they used from a list of ten options (e.g., fruit, tobacco, menthol) across
the first four assessments and reported past 6-month and past 30-day e-cigarette and combustible
cigarette use (yes/no) across the subsequent follow-up assessments (two through five). E-
cigarette flavor type (sweet vs. non-sweet vs. both) and total number of flavors vaped (range: 0-
10) were treated as time-varying predictors of past 6-month and past 30-day e-cigarette and
combustible cigarette use in repeated measure generalized linear mixed models. Polytomous
regression models assessed associations of e-cigarette flavor and dual use (i.e., concurrent
smoking and vaping). RESULTS: After adjustment for sociodemographic characteristics,
baseline past 30-day frequency of smoking and vaping and e-cigarette nicotine concentration,
any use of sweet-flavored e-cigarettes (vs. only non-sweet) was associated with increased odds
of persistent past 6-month (OR [95% CI] = 2.40 [1.32, 4.35]) and past 30-day use of e-cigarettes
(OR [95% CI] = 2.81 [1.33, 5.93]) across the two-year follow-up period. Each additional total
flavor vaped was associated with increased odds of persistent past 30-day (OR [95% CI] = 1.22
23
[1.12, 1.32]) and past 6-month (OR [95% CI] = 1.31 [1.20, 1.43]) vaping. Use of sweet-flavored
e-cigarettes was not associated with combustible cigarette smoking (ps > 0.50) or dual use (ps =
0.06 – 0.29). CONCLUSIONS: Regulations that restrict the availability of sweet-flavored e-
cigarettes and limit the wide variety of flavorings currently sold may decrease e-cigarette use
among youth. Future research should examine mechanisms through which flavored e-cigarettes
may maintain persistent e-cigarette use and if flavorings increase risk of transition to
combustible tobacco products.

24
INTRODUCTION

Electronic cigarettes (e-cigarettes) are currently the most commonly used tobacco product
(e.g., combustible cigarettes, cigarillos) among U.S. youth (Johnston et al., 2017; Singh, 2016).
The 2016 Surgeon General’s Report on e-cigarette use (vaping) among youth and young adults
recognized vaping as a major public health issue (Murthy, 2017), as the adolescent brain is
particularly vulnerable to the addictive and harmful effects of nicotine such as cognitive deficits,
reduced impulse control and mental health problems (England, Bunnell, Pechacek, Tong, &
McAfee, 2015). Furthermore, a growing body of evidence demonstrates that e-cigarette use
among nonsmoking youth is associated with greater risk of future combustible cigarette initiation
(Soneji et al., 2017) and increased frequency of past 30-day combustible cigarette smoking
following initiation of smoking (Leventhal et al., 2016). Accordingly, researchers and public
health experts have expressed concern that adolescent vaping is becoming a dangerous epidemic
that may endanger gains made in tobacco control (Kong & Krishnan-Sarin, 2017).
A review of the chemosensory science literature indicates that youth (vs. adults) have a
strong preference for sweet tastes and flavorings (Hoffman et al., 2016), and tobacco industry
documents demonstrate that adolescents are particularly susceptible to flavored tobacco products
(Carpenter et al., 2007; Carpenter et al., 2005). The 2009 Family Smoking Prevention and
Tobacco Control Act prohibited the production and sale of combustible cigarettes and several
other tobacco products with characterizing flavors other than menthol (and traditional tobacco),
leading to reductions in youth smoking and the overall prevalence of tobacco product use
(Courtemanche, Palmer, & Pesko, 2017). However, despite the success of this ban, e-cigarettes
are currently available in a wide variety of sweet flavorings (Zhu et al., 2014), many of which
include marketing descriptions and features (e.g., cartoons) designed specifically to appeal to
25
youth (Allem et al., 2018; Jackler & Ramamurthi, 2016; Kirkpatrick et al., 2017). In 2016 e-
cigarettes were classified as a tobacco product by the U.S. Food and Drug Administration
(FDA), granting the FDA regulatory authority over e-cigarette devices and their components, but
no final decision was made regarding restricting or eliminating the availability of flavored e-
cigarettes (Food & Drug Administration, 2016).
The availability of flavored e-cigarettes is cited as a primary reason for vaping by youth
(Hong et al., 2017; Kong et al., 2014; Patrick et al., 2016; Tsai, 2018), and adolescents perceive
flavored e-cigarettes to be less harmful and addictive than unflavored e-cigarettes (Cooper,
Harrell, Pérez, Delk, & Perry, 2016; Pepper et al., 2016)—a major risk factor for e-cigarette use
(Barrington-Trimis et al., 2015). Controlled laboratory studies demonstrate that sweet-flavored
(vs. tobacco-flavored) e-cigarettes are appealing due to their attractive sensory properties
(Goldenson et al., 2016; Kim et al., 2016), and qualitative evidence suggests that flavored e-
cigarettes may mask the harshness of nicotine (Kim, Davis, Dohack, & Clark, 2016; Soule et al.,
2016). Epidemiological data from national samples demonstrate that the vast majority of
adolescents initiate vaping with flavored e-cigarettes and subsequently use flavored e-cigarettes
during regular use (Ambrose et al., 2015; Villanti et al., 2017). In the 2014 Population
Assessment of Tobacco and Health (PATH) study, 81.0% of adolescent e-cigarette ever-users
and 85.3% of past 30-day e-cigarette users reported that the first e-cigarette they used was
flavored (Ambrose et al., 2015), and in the 2014 National Youth Tobacco Survey (NYTS),
63.3% of past 30-day vapers used flavored e-cigarettes (Corey et al., 2014).
Despite their popularity and widespread use, there is little longitudinal data regarding the
association between use of sweet-flavored e-cigarettes and persistent vaping among adolescents.
In a cross-sectional study of Connecticut youth, sweet-flavored e-cigarette use and the total
26
number of flavors preferred was associated with greater frequency of past 30-day vaping
(Morean et al., 2018), and in a prospective analysis initial use of e-cigarettes due to appealing
flavorings was associated with more persistent and frequent e-cigarette use at a 6-month follow-
up (Bold et al., 2016). Additionally, in a 2015 study of Texas youth, 78% of flavored e-cigarette
users stated they would no longer vape if flavored e-cigarettes were not available (Harrell et al.,
2017).
It is also unknown if use of flavored e-cigarettes is prospectively associated with
subsequent combustible cigarette smoking among youth. In a national cross-sectional survey,
use of flavored e-cigarettes among youth never-smokers was associated with increased
susceptibility to combustible cigarette smoking (Chen et al., 2017), and adolescent smokers who
used flavored e-cigarettes (vs. youth who used unflavored e-cigarettes and non-users) were less
likely to report intentions to quit smoking (Dai & Hao, 2016). Thus, use of flavored e-cigarettes
may increase the likelihood of combustible cigarette smoking among youth. In this prospective
study we hypothesized that use of sweet-flavored e-cigarettes (vs. non-sweet) and a greater total
number of e-cigarette flavors would be positively associated with subsequent vaping and
smoking across a series of follow-up assessments during the last two years of high school.

METHODS

Participants
Participants were 10
th
grade students from 10 high schools in the Los Angeles, CA
metropolitan area followed as part of a prospective cohort study of substance use and mental
health (Leventhal et al., 2015). Data were collected and processed via paper questionnaires at
the participants’ high schools during eight semiannual assessments beginning in fall 2013 (when
students was beginning 9
th
grade) through the end of their fourth year of high school (spring of
27
2017). Students not in class on the day of the assessment completed internet or telephone
surveys. A total of 3,396 participants enrolled in the study; overall retention throughout the
entire study was 92.5%. Flavored e-cigarette use was first assessed at the fourth wave of the
study when the cohort was in 10
th
grade (spring of 2015; baseline for his report). The follow-up
period consisted of four subsequent semi-annual assessments, resulting in a total of 5
assessments over an approximately 2.5-year period. The analytic sample included students who
provided valid data for the flavor they used in their e-cigarette use during at least one of the first
four assessments as well as past 6-month or past 30-day e-cigarette use at the next 6-month
follow-up assessment (N=564; Figure 3).

Ethics Statement
The University of Southern California Institutional Review Board approved this study.
Written or verbal parental consent was obtained and all students assented to participation.

Measures
Sweet-Flavored e-Cigarette Use
At the first four assessments participants selected all e-cigarette flavorings (i.e., select all
that apply format) that they had vaped during the past 30 days, answering the question, “Which
flavors did you usually use in your e-cigarette?” The ten response
options included: fruit, candy, sweet, buttery, blends/combinations, flavorless, tobacco, menthol,
mint or wintergreen and other flavor (fill-in-the-blank) based upon prior research (Krüsemann et
al., 2018; Yingst et al., 2017). The individual flavor names provided by participants who
selected the “other” option were coded manually. Based on flavor classification schemas,
28
menthol was considered a ‘non-sweet flavor’ (Krüsemann et al., 2018; Yingst et al., 2017).
Three mutually exclusive flavor categories were created: (1) use of only sweet flavors (i.e., fruit,
candy, sweet, buttery, blends/combinations); (2) use of only non-sweet flavors (i.e., tobacco,
menthol, mint, flavorless; and (3) use of both sweet and non-sweet flavored e-cigarettes. From
these three groups two mutually exclusive flavor categories were created to further parse the
effects of sweet-flavored e-cigarettes: (1) use of any sweet flavor; and (2) use of only non-sweet
flavors (i.e., tobacco, menthol/mint and flavorless). The total number of flavors participants
reported using was also calculated (range 1-10) and used as a predictor in additional analyses.

Past 6-Month e-Cigarette and Combustible Cigarette Use
At each assessment items based on the Monitoring the Future (MTF; Johnston et al.,
2017) and Youth Risk Behavior Surveillance (YRBS; Eaton et al., 2010) surveys assessed past 6-
month use of e-cigarettes and combustible cigarettes (yes/no). Past 6-month combustible
cigarette use was assessed with the question, “Have you ever used cigarettes in your life?”;
participants who responded, “Yes, in the last 6 months” were classified as past 6-month smokers.
Two separate questions were used to assess past 6-month use of e-cigarettes, as evidence
indicates that youth use e-cigarettes both with and without nicotine (Miech, Patrick, O'Malley, &
Johnston, 2016). At all assessments participants reported whether they had used a: (1)
“Electronic cigarette for nicotine;” and (2) “Electronic cigarette without nicotine or hash oil”
(i.e., just flavoring) in the past 6-months; participants who responded affirmatively to either
question were classified as past 6-month e-cigarette users.

29
Past 30-Day e-Cigarette and Combustible Cigarette Use
Past 30-day combustible cigarette use was assessed with the question, “In the last 30
days, how many total days have you used a cigarette?”; response options included eight ordinal
intervals of past 30-day cigarette frequency: 0 days, 1-2 days, 3-5 days, 6-9 days, 10-14, 15-19
days, 20-24, 25-29 days, and all 30 days. Past 30-day e-cigarette use was assessed with two
questions, “In the last 30 days, how many total days have you used a Electronic cigarette for
nicotine?” and “In the last 30 days, how many total days have you used a Electronic cigarette
without nicotine?” For both tobacco products a binary past 30-day use variable was created by
dichotomizing the eight response options (yes/no). Answers for the two e-cigarette questions
were combined to form a composite past 30-day e-cigarette use measure, as described above for
past 6-month use.

Covariates
Demographic characteristics including gender, age, race/ethnicity (Hispanic, White,
Asian and Other Race) and highest level of parental education (college degree or greater vs.
some college or less) were assessed with self-report measures at baseline and were included as a
priori covariates. Baseline e-cigarette nicotine concentration level was assessed with the
question, “What level of nicotine (strength of e-liquid or juice) did you usually use in your e-
cigarette?” The response options included none (0 mg/mL), low (1-5 mg/mL), medium (6-17
mg/ mL), high (≥18 mg/mL), and “I don’t know.” This 5-level variable was dichotomized (no
nicotine [0 mg/mL] / any nicotine) and was included as a time-varying covariate. Baseline past
30-day frequency of e-cigarette and combustible cigarette use at each of the first four time points
were transformed into three-level variables: (1) no use (0 days); (2) infrequent use (1-2 days);
30
and (3) frequent use (≥ 3 days). These variables were included as time-varying covariates to
control for baseline frequency of past 30-day e-cigarette and combustible cigarette use (e.g., past
30-day frequency of e-cigarette use at the first assessment was included as a covariate in the
prediction of past 6-month e-cigarette use at the second assessment).
e-Cigarette device type (i.e., cig-a-like, mid-size, Mod) was only assessed at the first
follow-up assessment, and is included in comparisons of baseline data for descriptive purposes.

Data Analysis
Preliminary analyses involved comparing study covariates by baseline e-cigarette flavor
and calculating descriptive statistics for sociodemographic characteristics and tobacco product
use outcomes across all assessments for participants included in the analytic sample. The
primary analyses consisted of a series of repeated measures generalized linear mixed models
with a logit link function (McCulloch & Neuhaus, 2001). E-cigarette flavor across the first four
time points was included as a time-varying regressor with past 6-month or past 30-day tobacco
product use at the subsequent assessment as the dependent variable (e.g., sweet-flavored e-
cigarette use at the first assessment predicted past 6-month e-cigarette use at the second
assessment, sweet-flavored e-cigarette use at the second assessment predicted past 6-month e-
cigarette use at the third assessment). Participants who exclusively used non-sweet-flavored e-
cigarettes served as the reference group in all analyses, and participant’s school was treated as a
random effect. Additional models that utilized the total numbers of e-cigarette flavors vaped as a
continuous time-varying predictor were also tested. All models were fit with and without
adjustment for covariates described above. Missing covariate data was addressed with multiple
imputation using the Markov-chain Monte Carlo method (Rubin, 2004).
31
After testing the main effects of sweet-flavored e-cigarette use, effect modification by
gender was assessed by including an e-cigarette flavor × gender interaction term in all adjusted
models. To assess dual product use (i.e., concurrent use of e-cigarettes and combustible
cigarettes at the same time point) a three-level dual-use variable was created (0 = no tobacco
product use; 1 = use of e-cigarettes or combustible cigarettes; 2 = use of both e-cigarettes and
combustible cigarettes) for both the past 6-month and past 30-day outcomes at each time point.
A series of repeated-measure polytomous (multinomial) regression models tested if there were
significant differences in the association of sweet-flavored e-cigarette use with the use of 1
tobacco products (vs. 0 tobacco products) and dual use (vs. use of only 1 tobacco product or 0
tobacco products) across the follow-up assessments. All analyses were conducted in SPSS
version 24 with alpha level set to 0.05 and results reported as Odds Ratios (OR+95% confidence
intervals [CIs]).

RESULTS
There were no significant differences in baseline participant characteristics by baseline e-
cigarette flavor type (Table 1; ps > 0.21). Sample descriptive statistics, the proportion of
participants that used sweet-flavored e-cigarettes and past 6-month and past 30-day tobacco
product use at each time point are displayed in Table 2. Overall, the sample (N=564) was
composed of roughly equivalent numbers of males and females (50.7% male), slightly less than
half of the sample (47.9%) were of Hispanic ethnicity and had parents who graduated college or
obtained more education (46.7%), and the average age at the baseline assessment was 16.13 (SD
= 0.44). The proportion of participants who used any sweet-flavored e-cigarettes ranged from
85.9% to 94.7% across the four follow-up assessments (Table 2). Across all follow-up time
32
points, past 6-month dual use of e-cigarettes and combustible cigarettes ranged from 21.6%–
32.6% (Table 2).

Association of e-Cigarette Flavor and Persistent Past 6-Month and 30-Day Tobacco
Product Use
After adjustment for all covariates listed above, exclusive use of sweet-flavored e-
cigarettes (OR [95% CI] = 2.24 [1.23, 4.07]) and combined use of both sweet-flavored and non-
sweet-flavored e-cigarettes (OR [95% CI] = 3.20 [1.60, 6.41]), compared to exclusive use of
non-sweet-flavored e-cigarettes, were significantly associated with greater odds of persistent past
30-day e-cigarette use at the subsequent 6-month follow-up assessment across the study period
(Table 3). Similarly, compared to exclusive use of non-sweet-flavored e-cigarettes, the odds of
persistent past 6-month e-cigarette use were significantly greater for participants who exclusively
used sweet-flavored e-cigarettes (OR [95% CI] = 2.60 [1.23, 5.51] and those who used both
sweet and non-sweet flavors (OR [95% CI] = 3.57 [1.59, 8.01]). There were no significant
differences in the associations of exclusive use of sweet-flavored e-cigarettes and combined use
of sweet- and non-sweet-flavored e-cigarettes and persistent vaping (ps = 0.12 – 0.15).
Any sweet-flavored e-cigarette use (vs. exclusive use of non-sweet flavors) was
significantly associated with persistent past 30-day e-cigarette use (OR [95% CI] = 2.81 (1.33,
5.93]) and past 6-month e-cigarette use (OR [95% CI] = 2.40 [1.32, 4.35]). Neither exclusive
use of sweet-flavored e-cigarettes nor combined use of both sweet and non-sweet flavored e-
cigarettes (vs. exclusive use of non-sweet e-cigarettes) were associated with subsequent past 6-
month or past 30-day combustible cigarette smoking in the adjusted models (ps > 0.50; Table 3).
33
In the fully-adjusted models, each 1-flavor increase in the total number of flavors vaped
was significantly associated with greater odds of persistent past 30-day (OR [95% CI] = 1.22
[1.12, 1.32]) and past 6-month (OR [95% CI] = 1.31 [1.20, 1.43]) e-cigarette use across the study
period. However, after adjustment for covariates the total number of flavors vaped was not
associated with greater odds of past 30-day or past 6-month cigarette smoking at the subsequent
follow-up assessment (ps > 0.14).

Association of Sweet-Flavored e-Cigarette Use and Subsequent Dual Use
In the fully-adjusted polytomous regression model, there were no significant associations
between sweet-flavored e-cigarette use and past 6-month or past 30-day dual use (vs. use of no
tobacco products) or dual use (vs. use of one tobacco product; ps = 0.06–0.29; Table 4).
Combined use of both sweet- and non-sweet-flavored e-cigarettes was significantly associated
with past 30-day use of only one tobacco product (vs. no tobacco product use) across the follow-
up time points (OR [95% CI] = 2.68 [1.16, 6.23]).

Sweet-Flavored e-Cigarette Use × Gender Interaction
There were no significant interactions between e-cigarette flavor and gender in the
association of sweet flavored e-cigarette use and subsequent past 30-day or past 6-month e-
cigarette use (ps > 0.53), cigarette smoking (ps > 0.66) or dual use (ps > 0.20).

DISCUSSION
In this prospective study, adolescents who vaped sweet-flavored e-cigarettes (vs. those
who exclusively vaped non-sweet flavors) and used a greater total number of e-cigarette flavors
34
were more likely to report persistent past 6-month and past 30-day e-cigarette use at the
subsequent follow-up assessment across the two-year study period. The results of this study
extend the extant evidence regarding the use of flavored e-cigarettes among adolescents—that
has primarily focused on initiation of e-cigarette use—to encompass a critical period of
development during which patterns of tobacco product use become ingrained (Eissenberg &
Balster, 2000). However, our hypothesis that use of sweet-flavored e-cigarettes would be
associated with subsequent combustible cigarette smoking was not supported, and use of sweet-
flavored e-cigarettes was also not associated with dual use of e-cigarettes and combustible
cigarettes.
E-cigarette devices and their components (i.e., e-liquids) comprise a broad array of
heterogeneous products, with several modifiable product characteristics such as flavor and
nicotine concentration that modulate the vaping experience and appeal to youth (Camenga et al.,
2018; Shang et al., 2017; Zare et al., 2018). Given that e-cigarettes now fall under the regulatory
authority of the FDA (Food & Drug Administration, 2016), it is important to identify specific
product characteristics that may contribute to continued e-cigarette use following initiation. For
example, recent evidence suggests that use of e-cigarettes with higher nicotine concentrations is
prospectively associated with increased past 30-day frequency of both vaping and smoking
(Goldenson, Leventhal, Stone, McConnell, & Barrington-Trimis, 2017). The current study
provides novel empirical data that highlights the importance of flavor as a key e-cigarette
product characteristic that may contribute to persistent vaping among youth. In conjunction with
epidemiological evidence (Courtemanche et al., 2017; Harrell et al., 2016; Villanti et al., 2017)
and self-reports that suggest that the elimination of characterizing flavors would likely reduce
35
youth e-cigarette use (Harrell et al., 2017), the longitudinal data presented in this study can
inform regulatory policy and tobacco prevention efforts.
Although e-cigarettes are believed to contain lower levels of carcinogens than
combustible cigarettes (Goniewicz et al., 2014; Shahab et al., 2017), they may adversely effect
the cardiovascular system and pulmonary function (Bhatnagar, 2016; McConnell et al., 2017;
Moheimani et al., 2017; Schweitzer, Wills, & Behner, 2017). There is concern that the chemical
constituents of sweet-flavored e-cigarette solutions, when aerosolized and inhaled, may be
particularly hazardous to respiratory health (Barrington-Trimis et al., 2014; Kaur, Muthumalage,
& Rahman, 2018). Toxicological evaluations of flavored e-liquids demonstrate that a large
percentage contain aldehydes, Diacetyl, Benzaldehyde and other harmful chemicals (Allen et al.,
2016; Klager et al., 2017; Kosmider et al., 2016), and preclinical evidence suggests that flavored
e-liquids may impair respiratory immune cell function, damage DNA and promote oxidative
stress (Clapp et al., 2017; Kaur et al., 2018). Additionally, a recent study found that youth who
use fruit-flavored e-cigarettes (vs. those who do not use fruit flavors) had higher urinary levels of
2-cyanoethylmercapturic acid, a metabolite of a toxic tobacco smoke constituent (Rubinstein,
Delucchi, Benowitz, & Ramo, 2018). Thus, persistent use of sweet-flavored e-cigarettes may be
particularly harmful to the health of youth.
We did not find a significant associations between use of sweet-flavored e-cigarettes and
combustible cigarette smoking or dual product use. These null findings may be explained by
differences in flavored e-cigarette use by smoking status. In a study of high school students in
Connecticut, combustible cigarette smokers used tobacco-flavored e-cigarettes at significantly
higher rates (26.1%) than never-smokers (3.7%) (Krishnan-Sarin, Morean, Camenga, Cavallo, &
Kong, 2014), and in surveys smokers report using tobacco and menthol-flavored e-cigarettes at
36
higher rates than nonsmokers (Berg, 2015; Farsalinos et al., 2013; Harrell et al., 2016). It may
be the case that smoking precedes e-cigarette use, leading to familiarity with and use of non-
sweet flavored e-cigarettes, however given the study’s sample size we were unable to address
this possibility. Research in larger samples is needed to further parse the association between
flavored e-cigarette use and smoking.
Regulatory policies that restrict the availability of flavored e-cigarettes may benefit the
public health of youth by reducing vaping, much like the 2009 ban on flavored combustible
cigarettes is believed to have contributed to reductions in youth tobacco use in the U.S.
(Courtemanche et al., 2017). Several municipalities (e.g., New York City, Chicago) have
reported reductions in flavored tobacco product use among youth after banning sales of
combustible flavored tobacco products (Farley & Johns, 2016). More recently the city of San
Francisco banned all flavored tobacco products, including e-cigarettes. Given evidence that few
adolescents are using e-cigarettes to quit or reduce smoking (Bold et al., 2017; Bold et al., 2016;
Patrick et al., 2016), it is unlikely that policies restricting flavored e-cigarettes would adversely
impact the public health of youth. In contrast such policies may improve public health by
reducing youth e-cigarette use.
Strengths of the study include the detailed assessment of flavored e-cigarette use, the
multiple longitudinal follow-up assessments, high rate of retention and a demographically
diverse sample. Limitations include the sample size, low prevalence of smoking and use of
survey self-reports. Similar to recent surveys over 90% of youth in this study used sweet-
flavored e-cigarettes, and the comparison group (i.e., youth who only used e-cigarettes with non-
sweet flavors) was relatively small (Harrell et al., 2016). Given low rates of smoking, we were
not able to stratify by smoking status or history. Future research in samples with larger numbers
37
of combustible tobacco product users are needed to assess the role that flavored e-cigarettes may
play in transitions from noncombustible to combustible tobacco products. Additionally, the
study did not assess or account for nicotine dependence, although we did control for e-cigarette
nicotine concentration. It is also possible that use of sweet-flavored e-cigarettes may serve as a
marker for another characteristic or risk factor that is maintaining vaping. The results are also
limited by the reliance on survey reports, and may be subject to inaccurate reporting and self-
report bias.

CONCLUSIONS
In this sample of high school students, use of sweet-flavored e-cigarettes and a greater
number of flavors was associated with increased odds of persistent e-cigarette use across a two-
year period. This study adds to the existing body of research that suggests that restricting the
availability of sweet-flavored e-cigarettes on a national level could reduce the prevalence of e-
cigarette use among youth. Future research should assess mechanisms through which sweet-
flavored e-cigarettes may maintain persistent vaping and influence transitions among tobacco
products in order to inform comprehensive tobacco prevention efforts.
38
Table 1. Sample Characteristics and Tobacco Product Use by Baseline e-Cigarette Flavor
Demographic Characteristics Total (N=326) Sweet-Flavor (N=305) Non-Sweet Flavor (N=21) Difference (p)
Male Gender 161 (52.8) 150 (49.2) 11 (52.4) 0.77
Age (years), M (SD) 16.08 (0.44) 16.07 (0.43) 16.16 (0.51) 0.37
Race/Ethnicity
0.99
Hispanic Ethnicity 165 (50.6) 154 (50.5) 11 (52.4)
White Race 60 (18.4) 56 (18.4) 4 (19.0)
Asian Race 55 (16.9) 51 (16.7) 4 (19.0)
Other Race 37 (11.3) 35 (11.5) 2 (9.5)
Parents Graduated College (vs. Less education) 115 (35.3) 106 (34.8) 9 (42.9) 0.21
Tobacco Product Use
Past 30-Day Frequency of e-Cigarette Use
0.75 Infrequent Past 30-Day e-Cigarette Use (1-2 days) 106 (45.1) 99 (44.8) 7 (50.0)
Frequent Past 30-Day e-Cigarette Use (≥ 3 days) 129 (54.9) 122 (55.2) 7 (50.0)
Past 30-Day Cigarette Smoking (yes/no) 92 (28.7) 86 (28.7) 6 (28.6) 0.99
Past 6-Month Cigarette Smoking (yes/no) 109 (33.4) 102 (33.9) 7 (33.3) 0.96
Past 30-Day Dual Use (yes/no) 77 (23.6) 71 (23.7) 6 (28.6) 0.66
Past 6-Month Dual Use (yes/no) 111 (34.2) 103 (34.2) 8 (38.1) 0.40
Use of e-Cigarette with Nicotine (vs. No nicotine) 132 (56.7) 125 (56.3) 7 (63.6) 0.63
e-Cigarette Device Type at 6-Month Follow-Up
1
st
Generation (cig-alike) 10 (5.9) 10 (6.2) 0 (0.0)
0.69
2
nd
Generation (midsize vape pen) 61 (36.3) 58 (36.0) 3 (42.9)
3
rd
Generation (APV/Mod) 83 (49.4) 79 (49.1) 4 (57.1)
I don’t know 14 (8.3) 14 (8.7) 0 (0.0)
Note. N = 326. Data presented as N (%) unless otherwise noted. Difference = tests of differences in sample characteristics between youth who vaped sweet-flavored e-
cigarettes and those who exclusively vaped non-sweet-flavored e-cigarettes with values from either c
2
(categorical variables) or ANOVA (continuous variables).

39
Table 2. Sample Descriptive Characteristics and Tobacco Product Use Across Follow-Ups
Baseline Demographic Characteristics
a
N (%) or M (SD)
Male Gender 286 (50.7)
Age (years) 16.13 (0.44)
Race/Ethnicity
Hispanic Ethnicity 262 (47.9)
White 118 (21.6)
Asian 104 (19.0)
Other 63 (11.5)
Parents Graduated College 226 (46.7)
Baseline Tobacco Product Use
Sweet-Flavored e-Cigarette Use 292 (94.2)
Past 6-Month e-Cigarette Use 267 (82.9)
Past 30-Day e-Cigarette Use 235 (73.0)
Past 6-Month Combustible Cigarette Use 122 (38.2)
Past 30-Day Combustible Cigarette Use 92 (28.7)
Past 6-Month Dual Use 111 (34.5)
Past 30-Day Dual Use 77 (24.0)
Tobacco Product Use at 6-Month Follow-Up
Sweet-Flavored e-Cigarette Use 213 (94.7)
Past 6-Month e-Cigarette Use 166 (53.5)
Past 30-Day e-Cigarette Use 98 (31.7)
Past 6-Month Combustible Cigarette Use 90 (29.1)
Past 30-Day Combustible Cigarette Use 59 (19.0)
Past 6-Month Dual Use 67 (21.6)
Past 30-Day Dual Use 35 (11.3)
Tobacco Product Use at 12-Month Follow-Up
Sweet-Flavored e-Cigarette Use 196 (91.6)
Past 6-Month e-Cigarette Use 126 (56.0)
Past 30-Day e-Cigarette Use 74 (33.5)
Past 6-Month Combustible Cigarette Use 68 (30.2)
Past 30-Day Combustible Cigarette Use 40 (18.1)
Past 6-Month Dual Use 51 (22.7)
Past 30-Day Dual Use 25 (11.5)
Tobacco Product Use at 18-Month Follow-Up
Sweet-Flavored e-Cigarette Use 159 (85.9)
Past 6-Month e-Cigarette Use 126 (58.9)
Past 30-Day e-Cigarette Use 72 (33.8)
Past 6-Month Combustible Cigarette Use 59 (28.1)
Past 30-Day Combustible Cigarette Use 38 (17.9)
Past 6-Month Dual Use 50 (23.8)
Past 30-Day Dual Use 25 (11.8)
Tobacco Product Use at 24-Month Follow-Up
Past 6-Month e-Cigarette Use 115 (62.2)
Past 30-Day e-Cigarette Use 79 (43.2)
Past 6-Month Combustible Cigarette Use 74 (40.2)
Past 30-Day Combustible Cigarette Use 54 (29.3)
Past 6-Month Dual Use 60 (32.6)
Past 30-Day Dual Use 42 (23.0)
Note.
a
N=564 participants. Denominators may be less than totals in column heads due to missing data.

40
Table 3. Association of e-Cigarette Flavor and Subsequent Tobacco Product Use across Follow-Up

e-Cigarettes Combustible Cigarettes
Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)

Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI) Past 6-Month Tobacco Product Use
Non-Sweet Only
Ref Ref Ref Ref
Sweet-Only
2.41 (1.37, 4.22)
**
2.24 (1.23, 4.07)
**
0.92 (0.51, 1.67) 0.79 (0.38, 1.64)
Both Sweet and Non-Sweet
4.35 (2.25, 8.40)
†
3.20 (1.60, 6.41)
**
1.08 (0.55, 2.13) 1.02 (0.54, 1.94)
Any Sweet
2.69 (1.54, 4.71)
**
2.40 (1.32, 4.35)
**
0.95 (0.53, 1.71) 0.97 (0.52, 1.83)
Past 30-Day Tobacco Product Use

Non-Sweet Only
Ref Ref Ref Ref
Sweet-Only
2.50 (1.24, 5.03)
*
2.60 (1.23, 5.51)
*
1.00 (0.51, 1.99) 0.88 (0.38, 2.02)
Both Sweet and Non-Sweet
4.72 (2.19, 10.14)
†
3.57 (1.59, 8.01)
*
1.11 (0.51, 2.42) 1.20 (0.57, 2.53)
Any Sweet
2.87 (1.43, 5.78)
**
2.81 (1.33, 5.93)
**
1.03 (0.52, 2.02) 1.12 (0.54, 2.32)

Note. N=561-564 (926-934 observations).
a
Adjusted for age, gender, race, highest level of parental education, baseline past 30-
day frequency of e-cigarette use (time-varying), baseline past 30-day frequency of cigarette smoking (time-varying) and
baseline e-cigarette nicotine concentration (time-varying).
*
p < 0.05.
**
p < 0.01.
†
p < 0.001.

41

Table 4. Associations between Sweet-Flavored e-Cigarette Use and Single and Dual Product Use

Number of Tobacco Products Used at 6-Month Follow-Up

Use of Only 1 Product (vs. 0)

Dual Use (vs. 0 Products)

Dual Use (vs. 1 Product)
Past 6-Month Tobacco Product Use
Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)
Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)
Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)
Non-Sweet Only
Ref Ref

Ref Ref

Ref Ref
Sweet-Only 1.66 (0.92, 3.00) 1.40 (0.75, 2.64) 1.75 (0.86, 3.55) 1.95 (0.88, 4.31) 1.05 (0.49, 2.24) 1.01 (0.42, 2.45)
Both Sweet and Non-Sweet 2.98 (1.48, 5.99)
**
2.02 (0.97, 4.24) 3.18 (1.40, 7.21)
**
2.08 (0.84, 5.16) 1.05 (0.46, 2.43) 1.37 (0.61, 3.08)
Any Sweet 1.83 (1.02, 3.29)
*
1.94 (0.88, 4.26) 1.95 (0.97, 3.92) 1.50 (0.80, 2.81) 1.05 (0.50, 2.23) 1.28 (0.58, 2.85)
Past 30-Day Tobacco Product Use
Non-Sweet Only
Ref Ref

Ref Ref

Ref Ref
Sweet-Only 1.99 (0.98, 4.05) 1.97 (0.91, 4.27) 1.52 (0.65, 3.57) 1.93 (0.74, 5.06) 0.66 (0.22, 1.48) 0.71 (0.23, 2.15)
Both Sweet and Non-Sweet 3.74 (1.71, 8.16)
**
2.68 (1.16, 6.23)
*
2.46 (0.95, 6.36) 1.88 (0.65, 5.39) 0.75 (0.27, 2.06) 0.97 (0.34, 2.77)
Any Sweet 2.26 (1.12, 4.57)
*
2.12 (0.99, 4.57) 1.67 (0.72, 3.90) 1.89 (0.73, 4.88) 0.73 (0.27, 2.00) 0.89 (0.32, 2.49)

Note. N=561-564 (926-934 observations). In each polytomous regression model use of sweet-flavored e-cigarettes was the regressor variable and use of zero or one
tobacco product was the reference group.
a
Adjusted for age, gender, race, highest level of parental education, baseline past 30-day frequency of e-cigarette use (time-varying), baseline past 30-day frequency of
cigarette smoking (time-varying) and baseline e-cigarette nicotine concentration (time-varying).
*
p < 0.05.
**
p < 0.01.
†
p < 0.001.

42

Table 5. Associations between Total Number of e-Cigarette Flavors Used and Tobacco Product Use
Regressor = Total Number of e-Cigarette
Flavors Used (0-10)
e-Cigarettes Combustible Cigarettes
Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)

Unadjusted
OR (95% CI)
Adjusted
a
OR (95% CI)
Past 6-Month Tobacco Product Use
2.02 (1.87, 2.18)
†
1.31 (1.20, 1.43)
†
1.55 (1.43, 1.67)
†
1.07 (0.98, 1.17)
Past 30-Day Tobacco Product Use
2.05 (1.92, 2.19)
†
1.22 (1.12, 1.32)
†
1.56 (1.46, 1.66)
†
1.04 (0.94, 1.15)

Note. N=561-564 (926-934 observations).
a
Adjusted for age, gender, race, highest level of parental education, baseline past 30-
day frequency of e-cigarette use (time-varying), baseline past 30-day frequency of cigarette smoking (time-varying) and
baseline e-cigarette nicotine concentration (time-varying).
*
p < 0.05.
**
p < 0.01.
†
p < 0.001.

43
Figure 3. Participant Accrual and Analytic Sample Flow Diagram

Note. Figure displays the analytic sample of eligible participants with available e-cigarette flavor at one time-point
and subsequent tobacco product use data at the subsequent time-point across the follow-up period.

Total Eligible Participants (N=4,100)
Final Analytic Sample (N=564)
No Active Parental Consent (N=478)
No Student Assent (N=226)
Enrolled in Study (N=3,396)
Completed Baseline Assessment (N=3,292)
Declined to Participate (N=12)
Lost to Follow-Up (N=92)
Note. Figure displays the analytic sample of eligible participants with available ADHD and tobacco product use data who never
used tobacco products at baseline.

Missing e-Cigarette Flavor Data (N=2,599)
Missing Tobacco Product Use Data During Follow-Up (N=129)
44
CHAPTER 3: EFFECTS OF SWEET-FLAVORED E-CIGARETTES ON SMOKING
REINSTATEMENT IN NICOTINE-DEPRIVED SMOKERS

ABSTRACT

Background: Electronic cigarettes (e-cigarettes) are considered to be less harmful than
combustible cigarettes, and could potentially help smokers reduce or quit smoking by switching
to a lower harm product. Identifying e-cigarette product characteristics that prevent smoking
relapse may inform clinical treatment and regulatory policies designed to decrease smoking.
Sweet flavorings have been shown to enhance e-cigarette product appeal and may reduce
motivation to smoke during tobacco abstinence. In this within-subjects laboratory model of
smoking relapse, we hypothesized that the administration of a sweet-flavored e-cigarette (vs.
tobacco-flavored) would decrease motivation to reinstate smoking and self-reported tobacco
withdrawal symptoms following overnight tobacco abstinence. Methods: E-cigarette-naïve
daily smokers (N=37; 32.4% female; mean age=55.2) attended two laboratory sessions after 16-
hours of tobacco abstinence. Participants self-administered an experimenter-provided e-cigarette
with nicotine in which only flavor was manipulated (sweet-flavored vs. tobacco-flavored).
Motivation to reinstate smoking was assessed with a behavioral task in which participants chose
between smoking and earning money; nicotine withdrawal symptoms were assessed with
validated subjective measures. Multilevel models tested differences between the two flavor
conditions on all smoking reinstatement and withdrawal symptom outcomes. Results: There
were significant differences in motivation to reinstate smoking between the two flavor
conditions. Participants were more likely to delay smoking (mean difference: Sweet – Tobacco
[95% CI] = 10.62 minutes [3.03, 18.22]; p =.007) and smoke fewer cigarettes (Mean Difference:
Sweet – Tobacco [95% CI] = 0.62 cigarettes [0.01, 0.76]; p =.04) after administering the sweet-
flavored (vs. tobacco-flavored) e-cigarette. There were no significant differences in subjective
45
withdrawal symptoms between the flavor conditions (ps = 0.19 – 0.88), although the sweet-
flavor condition non-significantly decreased anhedonia (p = 0.06). Conclusions: Sweet-flavored
(vs. tobacco-flavored) e-cigarettes may affect motivation to reinstate smoking in nicotine-
deprived smokers. Additional research is needed to determine if e-cigarettes are viable cessation
aids and to extend this assessment to the wide variety of flavorings currently available on the
market.

46
INTRODUCTION
Cigarette smoking remains the leading cause of preventable morbidity and mortality in
the United States, despite significant public health efforts and advances in clinical smoking
cessation treatment (Health & Services, 2014). Nicotine is the primary psychoactive constituent
of combustible cigarettes that maintains tobacco dependence and cigarette smoking (Benowitz,
2008; Benowitz, 1996). Nicotine withdrawal, a constellation of adverse psychobiological
symptoms (e.g., irritability, increased negative affect) that emerge following cigarette abstinence
(Hughes, 1994; Hughes & Hatsukami, 1986), mediate the behavioral motivation to reinstate
smoking and inhibit cessation efforts among regular smokers (Aguirre et al., 2015; Hughes,
2007; Piasecki, 2006). While nicotine replacement therapies (NRTs; e.g., nicotine patch, gum
and nasal spray) have existed since the 1960’s, their long-term effectiveness at smoking
cessation remains relatively low among smokers with high levels of nicotine dependence (Stead
et al., 2008), and the majority of smokers continue to attempt to quit without any therapeutic aid
(Caraballo, Shafer, Patel, Davis, & McAfee, 2017; Edwards, Bondy, Callaghan, & Mann, 2014).
New and innovative treatments are needed to reduce the public health burden of tobacco and
advance smoking cessation treatment in the 21
st
century.
Electronic cigarettes (e-cigarettes) deliver nicotine via aerosolized non-combusted
vapors, and are considered to be less harmful than combustible cigarettes as they contain fewer
carcinogenic and toxic constituents (Goniewicz et al., 2017; Goniewicz et al., 2014; Hajek, Etter,
Benowitz, Eissenberg, & McRobbie, 2014; Polosa et al., 2013; Romagna et al., 2013; Stephens,
2017). Adult smokers report using e-cigarettes (vaping) to reduce or quit smoking (Caraballo et
al., 2017; Farsalinos, Romagna, Tsiapras, Kyrzopoulos, & Voudris, 2014; Rutten et al., 2015),
and laboratory and clinical research demonstrate that use of e-cigarettes with nicotine can reduce
47
acute withdrawal symptoms (Dawkins & Corcoran, 2014; Dawkins et al., 2015; Dawkins et al.,
2012; Walele, Sharma, Savioz, Martin, & Williams, 2016) and may aid smoking cessation or
reduction efforts (Hartmann‐Boyce et al., 2016; Khoudigian et al., 2016). Preliminary evidence
also suggests that e-cigarettes without nicotine can reduce acute withdrawal symptoms and
craving for combustible cigarettes (Przulj et al., 2016; Tseng et al., 2016; Van Heel et al., 2017),
suggesting that, like combustible cigarettes, the non-pharmacological (i.e., sensorimotor)
properties of e-cigarettes may play a role in suppressing withdrawal symptoms (Rose, 2006;
Rose et al., 2010).
Evidence from the nicotine psychopharmacology, neuroscience and e-cigarette literature
suggest that sweet flavorings may be effective at reducing nicotine withdrawal (Beauchamp,
2016; Cohen et al., 1997; Cohen et al., 2010; Cortez-Garland et al., 2010; Helen, Dempsey,
Havel, Jacob, & Benowitz, 2017; Lenoir, Serre, Cantin, & Ahmed, 2007; Miao, Beach, Sommer,
Zimmerman, & Jordt, 2016). Sweet flavorings have been shown to activate
neuropharmacological reward pathways in the brain (Touzani et al., 2010), and during nicotine
withdrawal, the administration of confectionary chewing gum (vs. unflavored) has been shown to
reduce nicotine withdrawal symptoms (Cohen et al., 1997; Cohen et al., 2010; Cortez-Garland et
al., 2010).
E-cigarettes with flavors that simulate the sweetness and taste of candy and fruit are
widely available (Zhu et al., 2014) and are popular among both youth (Harrell et al., 2016) and
adult e-cigarette users (Berg, 2015; Kim et al., 2016). In surveys, former smokers who have
successfully substituted e-cigarettes for combustible cigarettes cite flavor as a key product
feature that differentiates e-cigarettes from combustible cigarettes and aids them in quitting or
reducing smoking (Cheney, Gowin, & Wann, 2016; Farsalinos et al., 2013; Christopher Russell
48
et al., 2017). Observational evidence suggests that use of flavored e-cigarettes (vs. tobacco and
menthol flavorings) may be associated with greater likelihood of successfully quitting smoking
(Tackett et al., 2015). Controlled laboratory studies demonstrate that sweet-flavored e-cigarettes
are appealing due to their attractive sensory effects (e.g., sensory sweetness) and increase the
rewarding properties of e-cigarettes (Audrain-McGovern et al., 2016; Goldenson et al., 2016;
Kim et al., 2016), and in a smoking reduction trial that utilized flavored e-cigarettes, cherry-
flavored e-cigarettes were preferred to tobacco-flavored e-cigarettes (Litt et al., 2016).
In its 2016 Deeming Regulations, the FDA noted that the appeal of flavored e-cigarettes
may enhance their use as harm reduction devices among combustible tobacco users seeking
lower harm substitutes, “We recognize that the availability of alternatives to traditional tobacco
flavors in some products (e.g., ENDS) may potentially help some adult users who are attempting
to transition away from combusted products” (Food & Drug Administration, 2016). The ability
to reduce withdrawal symptoms during tobacco abstinence is a key feature of nicotine
replacement products that aids smoking reduction and cessation (Kralikova, Novak, West,
Kmetova, & Hajek, 2013). Hence, data on the withdrawal-suppressive effects of flavored e-
cigarettes is needed to inform future regulatory decisions regarding the ongoing availability of
flavored e-cigarettes. In this behavioral pharmacology study, we tested the hypothesis that
sweet-flavored e-cigarettes (vs. tobacco-flavor) would reduce motivation to reinstate smoking
and nicotine withdrawal symptoms among e-cigarette-naïve adult smokers.

49
METHODS
Participants
Participants (N=37) were e-cigarette-naïve adult daily combustible cigarette smokers
recruited in the Los Angeles, CA metropolitan area via online advertisements (e.g., Clinical
Connection, Craigslist) and an existing database from previous laboratory smoking studies.
Inclusion criteria were: (1) age ≥ 21 years; (2) daily cigarette smoking (i.e., > 10 cig/day) for at
least the past two years; and (3) interest in trying e-cigarettes. Exclusion criteria were: (1) prior
use of e-cigarettes (i.e., self-report > 10 puffs lifetime, use on more than two occasions,
purchased own device); (2) current use of medications that impact nicotine withdrawal or
smoking (e.g., bupropion, varenicline, nicotine replacement therapy, anti-depressants,
anxiolytics); (3) current use of mentholated cigarettes; (4) pregnancy/breastfeeding; and (5) daily
use of other tobacco products (e.g., hookah, cigars). Smokers of mentholated cigarettes were
excluded to prevent bias related to the flavor manipulation as they may find tobacco-flavored e-
cigarettes aversive. All participants provided written informed consent and were compensated
for their participation. The University of Southern California Institutional Review Board
approved the study protocol.

Design
Participants attended a total of three laboratory sessions: an initial baseline visit followed
by two experimental sessions that each occurred after 16 hours of tobacco/nicotine deprivation.
In the two experimental visits, e-cigarette flavor was experimentally manipulated (sweet-
flavored vs. tobacco-flavored) according to a within-subject, double-blind, counter-balanced
design. Participants answered a battery of measures that assessed nicotine withdrawal
50
symptoms, before and after the controlled e-cigarette administration, and then completed a
behavioral smoking task that measured motivation to reinstate smoking (Figure 4).

Procedure
After a preliminary telephone screening, participants attended a baseline session in which
they provided an end-tidal breath sample for carbon monoxide (CO) measurement to confirm
daily smoking and study eligibility (i.e., CO > 10). Eligible participants completed
questionnaires assessing demographics and smoking history and practiced the e-cigarette
administration procedure (see standardized puffing procedure below) using the study e-cigarette
device with a flavorless e-liquid that did not contain nicotine (i.e., 0 mg/mL). Participants then
attended two randomized, counter-balanced experimental laboratory sessions, after completing
16-hours of tobacco product deprivation. Participants were informed that they could not use any
alcohol or drugs 24 hours prior to study visits to prevent masking of withdrawal symptoms, and
were also required to abstain from all nicotine/tobacco products 16-hours prior to the
appointment.
The experimental procedures for each session were identical, with only the randomly
assigned e-cigarette flavor condition (i.e., sweet vs. tobacco) varying. At the beginning of each
session, nicotine abstinence was biochemically confirmed (i.e., breath CO < 9 ppm) and alcohol
breath analysis was performed to verify participants were abstinent from alcohol (BAC = 0.000).
Participants first completed a 15-minute pre-administration assessment that included self-report
measures of nicotine withdrawal (i.e., affect and cigarette craving) as well as physiological
measures (i.e., heart rate and blood pressure).
51
After the pre-administration assessment was completed, the standardized e-cigarette
administration occurred, and was immediately followed by a 25-minute post-administration
assessment of e-cigarette subjective effects and measures of nicotine withdrawal symptoms and
cigarette craving. The standardized e-cigarette administration lasted 5-minutes and consisted of
an animated video that cued participants to inhale and exhale (10 total puffs) from the e-cigarette
device according to a schedule designed to approximate typical e-cigarette use patterns (i.e., 4-
second inhale, 1-second hold, 2-second exhale) (Helen et al., 2016; Yip & Talbot, 2013). Upon
completing all self-report measures of withdrawal and combustible cigarette craving, participants
began the behavioral smoking task followed by an hour-long rest period and dismissal from the
study (Figure 4).

Materials
All participants were provided with a Joyetech eGrip II, a recent-generation
commercially-available e-cigarette device, with resistance of 1.53Ω (ohms) and wattage held
constant at 10 watts. The sweet-flavored solution (‘Mardi Gras’ - described as, “sweet and
smooth with mixed berry flavors,” and the tobacco solution (‘Jamestown’ - described as, “bold,
smooth and similar to traditional tobacco”) were purchased from a domestic provider based on
consultation with the vendor. A tobacco-flavored solution (vs. flavorless) was selected as the
control as unflavored solutions have been shown to lack appeal among smokers (Audrain-
McGovern et al., 2016). The e-cigarette solutions both contained 3 mg/mL of nicotine, a dose
sufficient to deliver nicotine to the bloodstream given the power of the device (Hajek et al.,
2017; Ramôa et al., 2015), with a 50/50 propylene glycol/vegetable glycerin ratio. Heart rate
52
and blood pressure were assessed with a digital Sphygmomanometer monitor and breath CO
levels were assayed with a Bedfont Scientific Smokelyzer® breath CO monitor.

Measures
Baseline Characteristics
At baseline, demographic characteristics were assessed with an experimenter-created
questionnaire and the Smoking History Questionnaire assessed smoking frequency, use of other
tobacco products and prior quit attempts (Brown et al., 2002). The Fagerström Test of Nicotine
Dependence (FTND; Heatherton, Kozlowski, Frecker, & Fagerstrom, 1991) measured cigarette-
based nicotine dependence on a 10-point scale, and the brief version of the Wisconsin Inventory
of Smoking Dependence Motives (WISDM; Smith et al., 2010) assessed 11 multidimensional
motives for smoking (e.g., craving, positive reinforcement, negative reinforcement) with 37
items. The Sweet Taste Questionnaire (STQ) assessed participant’s preference for sweets and
sensitivity to the mood altering effect of sweets with 12-items that were answered on 7-point
response scales (range 7-84; Kampov-Polevoy, Alterman, Khalitov, & Garbutt, 2006).
Participants also completed the Alcohol Use Disorders Identification Test (AUDIT; Saunders,
Aasland, & WHO, 1987), a 10-item measure used to assess alcohol use problems, and the Drug
Abuse Screening Test (DAST; Skinner, 1982), a 10-item screening instrument to assess non-
alcohol, non-nicotine drug use and dependence.

Acute Subjective Vaping Effects
After the 10-puff e-cigarette administration, participants answered a series of questions
that assessed the appeal and sensory effects of the e-cigarette condition. Participants rated the
53
appeal of each e-cigarette with three questions: (1) “How much did you like the e-cigarette?”; (2)
“How much did you dislike the e-cigarette?”; and (3) “Would you use this e-cigarette again?”.
Participants also rated the attractive sensory effects with three questions: (1) “How sweet was the
e-cigarette”; (2) “How smooth was the e-cigarette?”; (3) “How much did you like the throat
hit?”; and the aversive sensory effects with two questions: (1) “How harsh was the e-cigarette?”;
and (2) “How bitter was the e-cigarette?” as in previous laboratory research (Goldenson et al.,
2016). The appeal and sensory effects outcomes were summed and averaged to form three
composite measures (Song, Lin, Ward, & Fine, 2013), with only “Dislike” being reverse-scored.
We adapted the Cigarette Rating Scale (CRS; Waters et al., 2003) to assess the psychological
reward of each e-cigarette flavor condition with five questions (i.e., “Did it help you
concentrate?”, “Did it calm you down?”, “Did it make you feel more awake?”, “Did it reduce
your hunger for food?”, “Did it make you feel less irritable?”) and one question assessed craving
reduction (“Did it immediately reduce your craving for cigarettes”?). All questions were
answered on 100-point visual analog scales (VAS) with anchors of “Not at All” and
“Extremely,” with the exception of willingness-to-use-again, which used anchors of “Not at all”
to “Definitely.”

Behavioral Measure of Motivation to Reinstate Smoking
Following the e-cigarette administration and questionnaires, participants completed a
behavioral-economic task that measured their ability to resist the desire to smoke cigarettes
under conditions in which it was advantageous to remain abstinent (McKee, 2009). In both
portions of the smoking task participants chose between two competing reinforcers—smoking
and earning money—quantifying their motivation to reinstate smoking (DeGrandpre, Bickel,
54
Higgins, & Hughes, 1994). The task began with the delay period in which participants were
presented with a box containing eight of their own usual-brand cigarettes (provided by the
participant) and were instructed that they could begin smoking at any time during the following
50 minutes. However, for each 5 minutes participants delayed smoking they earned $0.20 (for a
maximum of $2.00) that was paid to them at the end of their visit. The delay score, or latency to
smoke (range: 0-50 minutes), quantified participant’s ability to resist the urge to reinstate
smoking (i.e., the reward value of initiating tobacco product use relative to earning money).
The self-administration period began when participants indicated that they wished to
initiate smoking, or at the end of 50 minutes for participants who chose to wait the entire delay
period. During the self-administration period participants were instructed that they could smoke
as many or as few of their eight cigarettes as they wished during the 60-minute period, but for
each cigarette they smoked $0.20 would be subtracted from their initial total of $1.60. The
number of cigarettes purchased after being given the opportunity to initiate smoking (range: 0-8)
during the self-administration period reflected an additional aspect of the reward value of
smoking reinstatement.

Subjective Nicotine Withdrawal
Participants completed two measures of subjective nicotine withdrawal symptoms at both
the pre- and post-administration assessments. The 10-item Positive Affect Negative Affect
Schedule (PANAS-SF; Watson, Clark, & Tellegen, 1988) measured positive and negative affect,
and the short form of the Tobacco Craving Questionnaire (TCQ; Heishman, Singleton, &
Pickworth, 2008) assessed four dimensions of tobacco craving (i.e., emotionality, expectancy,
55
compulsivity, purposefulness). Heart rate and blood pressure were also assessed pre- and post-
administration.
After the e-cigarette administration, participants completed the Brief Questionnaire of
Smoking Urges (QSU; Cox, Tiffany, & Christen, 2001), a well-validated 10-item measure of
intention, urge and need to smoke cigarettes that includes two 5-item subscales: (1) desire for the
positive effects of smoking; and (2) desire for relief of negative affect (Tiffany & Drobes, 1991).
The Minnesota Nicotine Withdrawal Scale (MNWS; Hughes & Hatsukami, 1986) measured 11
DSM-IV nicotine withdrawal symptoms on 6-point response scales, the 23-item Wisconsin
Smoking Withdrawal Scale (WSWS; Welsch et al., 1999) assessed the severity of seven
individual withdrawal symptoms (i.e., anxiety, anger, hunger, concentration problems, craving,
sadness, sleep) and the Profile of Mood States (POMS; McNair, Lorr, & Droppleman, 1971) was
used to obtain measures of positive and negative affect as well as anxiety, sadness, and anger.
The state version of the Snaith-Hamilton Pleasure Scale (SHAPS; Franken, Rassin, & Muris,
2007) was used to assess current hedonic responsivity, as anhedonia may be considered a
symptom of nicotine withdrawal syndrome (Cook et al., 2015; Paolini & De Biasi, 2011).

Data Analysis
Preliminary analyses involved calculating descriptive statistics for all sociodemographic
and cigarette smoking characteristics. A multi-level data set was created in which participant
outcomes during each experimental session (i.e., subjective vaping effects, nicotine withdrawal,
motivation to reinstate smoking) were stratified by the within-subject e-cigarette flavor condition
(i.e., sweet vs. tobacco). Participant’s baseline CO level was compared to the CO readings from
56
the two experimental sessions to confirm a reduction in smoking from baseline (aggregated
across the two experimental sessions) with multi-level linear models.
Primary analyses utilized multilevel linear models or generalized linear mixed models
with an independent, fixed effect of flavor (i.e., sweet vs. tobacco) as the sole regressor to assess
the effect of e-cigarette flavor condition on subjective vaping effects, motivation to reinstate
smoking or nicotine withdrawal symptoms. The two behavioral smoking task outcomes were
tested in separate models; the temporal outcome from the delay period of the smoking delay task
(i.e., 0 – 50 minutes delayed) was analyzed as a continuous variable using multilevel linear
models. The outcome from the self-administration period of the smoking delay task (i.e., 0 – 8
cigarettes smoked) was analyzed using logistic regression generalized-linear mixed models
(McCulloch & Neuhaus, 2001) with a Poisson distribution for count data.
Each of the subjective vaping effects (i.e., appeal, attractive sensory effects, aversive
sensory effects) and measures of subjective nicotine withdrawal that were completed at the post-
administration assessment (i.e., QSU, MNWS, WSWS, POMS) were tested in separate
multilevel models. For the measures that were assessed at both the pre- and post-e-cigarette
administration (i.e., PANAS and TCQ), the pre-administration score was included as a covariate.
In all models the main effect of randomization order (i.e., whether participants were randomized
to the sweet- or tobacco-flavored e-cigarette condition first) was tested.
Lastly, we tested a series of meditational models to determine if the effects of e-cigarette
flavor on the two behavioral smoking task outcomes were mediated by the subjective vaping
effects. For each significant subjective vaping effect we report: (1) the total effect (i.e., effect of
flavor condition on behavioral smoking task outcomes); (2) the “A” path (i.e., effect of flavor
condition on subjective vaping effect mediator; (3) the “B” path (i.e., effect of subjective vaping
57
effect mediator on the behavioral smoking task outcome adjusting for flavor condition); (4) the
“indirect (mediated) effect (i.e., effect of flavor condition on behavioral smoking task outcome
that is accounted for via the subjective vaping effect mediator); (5) the ‘direct effect’ that is not
accounted for by the mediator (i.e., effect of the flavor condition on behavioral smoking task
outcome after statistically adjusting for the subjective vaping effect mediator); and (6) the
proportion of the total effect that is mediated. Mediational pathways were tested using
multilevel modeling techniques for clustered data (Krull & MacKinnon, 2001). Data were
analyzed using IBM SPSS Statistics Version 24 (IBM Corp., Armonk, NY) and Stata version
14.1 with alpha level set to 0.05.

RESULTS
Sample Characteristics
The sample was primarily composed of older adult (M [SD] age = 55.2 [7.6]), African-
American (56.8%), male (67.6%) smokers, with mild alcohol (Saunders et al., 1987) and drug
problems (Skinner, 1982) (Table 6). Over half (56.8%) of the sample completed some collegiate
education and 48.7% reported annual income of $15,000 or less. Participants reported, on
average, medium nicotine dependence on the FTND (Heatherton et al., 1991) (M [SD] = 6.2
[1.9]), smoked 14.8 (SD = 6.3) cigarettes per day and reported 11.6 (SD = 24.2) lifetime serious
quit attempts. The average age participants began smoking everyday was 19.2 (SD = 7.9), and
participants reported smoking for negative reinforcement (i.e., to ameliorate negative internal
states; WISDM-NR M [SD] = 9.2 [3.8]). There were significant reductions in breath CO from
baseline to both of the experimental sessions (ps < 0.001), and the CO values for the two
58
experimental sessions did not significantly differ (p = 0.88). Additionally, there were no
significant effects of randomization order for any of the outcomes (ps > 0.86).

Effects of e-Cigarette Flavor on Subjective Vaping Effects
There were significant main effects of the flavor manipulation (sweet vs. tobacco) on the
appeal and sensory effects of vaping (ps < 0.004). The sweet-flavored e-cigarette (vs. tobacco-
flavored) was rated as significantly more appealing (p = 0.004) and enhancing the psychological
reward of vaping (p = 0.001; Figure 6). The sweet-flavored e-cigarette condition was also rated
as possessing significantly greater attractive sensory effects than the tobacco-flavored e-cigarette
(p < 0.001) as well as significantly lower aversive sensory effects (p = 0.001; Figure 6). There
was no significant main effect of flavor on acute craving reduction (p = 0.93).

Effects of e-Cigarette Flavor on Motivation to Reinstate Smoking
There were significant main effects of e-cigarette flavor for both outcomes from the
behavioral smoking task: (1) the amount of time participants delayed the initiation of smoking;
and (2) the number of cigarettes purchased (ps < 0.05; Figure 5). In the sweet-flavor condition,
participants delayed the initiation of smoking an average of 27.5 minutes (SD = 21.1), whereas in
the tobacco-flavored condition participants delayed the initiation of smoking an average of 16.9
minutes (SD = 20.1). This difference in delaying the initiation of smoking was statistically
significant (Mean Difference: Sweet – Tobacco [95% CI] = 10.62 minutes [3.03, 18.22]; p
=.007; Figure 5, Panel A). During the 60-min self-administration portion of the task, participants
purchased a greater number of cigarettes in the tobacco-flavored (M [SD] = 1.86 [0.95]) vs.
sweet-flavored (M [SD] = 1.24 [0.83]) condition, and this difference was also statistically
59
significant (Mean Difference: Tobacco – Sweet [95% CI] = 0.62 cigarettes [0.01, 0.76]; p =.04;
Figure 5, Panel B).

Effects of e-Cigarette Flavor on Subjective Nicotine Withdrawal Symptoms
There were no significant differences in the vaping-induced withdrawal-suppressive
effects produced by the sweet-flavored (vs. tobacco-flavored) e-cigarette across the battery of
self-report measures used to assess craving for combustible cigarettes (i.e., TCQ, QSU) and
nicotine withdrawal symptoms (i.e., MNWS, PANAS, WSWS, POMS, SHAPS; Table 7).
However, differences between the two flavor conditions on the SHAPS approached statistical
significance (p = 0.06), with lower levels of anhedonia exhibited in the sweet-flavor condition
(Table 7). Scores on the four TCQ subscales (ps = 0.49 – 0.88; Table 7), the total QSU sum
score and the two QSU subscales that assessed rewarding effects and relief of negative affect,
respectively, did not significantly differ by flavor condition (ps = 0.52 – 0.64; Table 7).
Similarly, there were no significant differences in self-reported nicotine withdrawal symptoms
between the flavor conditions as measured by the MNWS (p = 0.66), PANAS negative affect (p
= 0.79) or positive affect subscales (p = 0.19) and WSWS overall scale (p = 0.72).

Mediation of Flavor Condition on Smoking Outcomes by Subjective Vaping Effects
The effect of sweet-flavor (vs. tobacco-flavor) on the behavioral smoking task outcomes
(i.e., delay time and number of cigarettes purchased) was not significantly mediated by any of
the subjective vaping effects (ps > 0.96; Table 8).

60
DISCUSSION
The present study assessed if the administration of a sweet-flavored e-cigarette (vs.
tobacco-flavored) among nicotine-deprived adult smokers reduced: (1) motivation to reinstate
smoking; and (2) subjective nicotine withdrawal symptoms. There were significant differences
in the two dimensions of smoking reinstatement assessed by the behavioral smoking task, such
that participants were significantly more likely to delay the initiation of smoking and smoke
fewer cigarettes after self-administering the sweet-flavored (vs. tobacco-flavored) e-cigarette. In
contrast, there were no significant differences between the two flavor conditions in subjective
(self-report) measures of withdrawal symptoms, craving for combustible cigarettes or
physiological effects (i.e., blood pressure, heart rate). Furthermore, the appeal and sensory
effects of the sweet-flavored e-cigarette condition did not mediate the association between flavor
and motivation to reinstate smoking.
Examining the effects of sweet-flavored e-cigarettes on smoking reinstatement and
withdrawal symptoms has important implications for smoking cessation treatment and tobacco
regulatory science. The FDA’s mission of promoting public health includes encouraging the
development of innovative products and treatments that are less harmful than combustible
cigarettes while remaining satisfying to smokers who need or want nicotine. In its 2016 deeming
regulations, the FDA’s Center for Tobacco Products (CTP) stated its need to consider,
“[E]merging evidence that some adults may potentially use certain flavored tobacco products to
transition away from combusted products” (Food & Drug Administration, 2016).
In the mediational analyses subjective appeal and sensory effects did not significantly
mediate reductions in motivation to reinstate smoking, suggesting that a mechanism other than
subjective appeal may underlie these behavioral changes. Laboratory research indicates that
61
vapers may alter their topography when using sweet-flavored e-cigarettes (i.e., exhibit greater
average puff duration when using a strawberry e-liquid vs. tobacco e-liquid; Helen, Shahid, Chu,
& Benowitz, 2018), and sweet-flavored e-cigarettes may modulate the PH of the e-liquid
affecting the pharmokinetics of nicotine delivery (Helen et al., 2017). Hence, the significant
reduction in motivation to reinstate smoking after administering the sweet-flavored e-cigarette
could result from the differences in the intake and absorption of nicotine. Future research is
needed to further explore this possibility and elucidate mechanisms that may reduce motivation
to reinstate smoking.
There are several possible explanations for why we did not find any significant effects of
e-cigarette flavor on subjective reports of nicotine withdrawal symptoms or craving for
combustible cigarettes, including the possibility that flavor does not affect withdrawal. Since all
participants received an active dose of nicotine, the effects of flavor on withdrawal may have
been masked by nicotine. While the sweet-flavored e-cigarettes (vs. tobacco-flavored) enhanced
the subjective vaping effects (e.g., appeal, sensory effects), these effects did not mediate the
association of flavor and motivation to reinstate smoking. These findings suggest that a
mechanism other than the acute appeal of flavored e-cigarettes may effect smoking reinstatement
behavior, much as drug-administration research with other addictive substances (i.e., cocaine)
demonstrates that self-administration behavior remains robust even in the absence of rewarding
subjective effects (Foltin et al., 2003; Haney, Collins, Ward, Foltin, & Fischman, 1999; Hart,
Ward, Collins, Haney, & Foltin, 2004).
It is also possible that objective measures of reinforcement and behavioral responses may
be more sensitive to the effects of flavor stimuli than self-report measures. The lack of
significant differences on the subjective withdrawal measures concord with a recent laboratory
62
study that did not find significant differences in subjective reports of nicotine withdrawal
symptoms between an apple-flavored and tobacco-flavored e-cigarette condition (Van Heel et
al., 2017). Preclinical and laboratory studies with smokers suggest that smoking behavior may
be particularly sensitive to non-nicotine stimuli, including flavor (Barrett, 2010; Wickham et al.,
2017). A study that assessed the rewarding and reinforcing effects of flavored e-cigarettes with
human subjects reported robust results from two behavioral tasks, with participants working
nearly six-times harder for a sweet-flavored e-cigarette (vs. flavorless) in a progressive ratio task
and self-administering the sweet-flavored e-cigarettes nearly twice as frequently during an ad lib
period (Audrain-McGovern et al., 2016). The discrepancy in these results highlight the
importance of including behavioral measures of appeal and smoking reinstatement behavior in
future research.
A number of researchers and experts in tobacco control state that the single most important
goal facing public health is the reduction or elimination of combustible tobacco product use
(Benowitz et al., 2017), and posit that e-cigarettes may offer a fruitful solution for achieving this
goal (Hajek, 2014; Nutt et al., 2014; Nutt et al., 2016). As such, there is concern that restricting
the availability of flavored e-cigarettes could discourage the substitution of combustible
cigarettes with noncombustible tobacco products such as e-cigarettes. In surveys and qualitative
reports former smokers report that restricting the availability of flavorings would make the
vaping less enjoyable and reduce the appeal of e-cigarettes among smokers seeking to substitute
e-cigarettes for combustible cigarettes (Barbeau et al., 2013; Farsalinos et al., 2013).
The results of a simulation study suggests that a ban on flavored e-cigarettes could increase
smoking rates and drive some vapers who formerly smoked back to smoking combustible
cigarettes (Buckell, Marti, & Sindelar, 2017). Furthermore, a recent study of adult smokers
63
found that use of flavored e-cigarettes was associated with lower daily intensity
of cigarette smoking (Buu, Hu, Piper, & Lin, 2018), and in a national sample of young adult
smokers smoking reduction or cessation was prospectively associated with use of flavored (vs.
tobacco-flavored) e-cigarettes (Chen, 2018). In online surveys adult e-cigarette users who
switched from smoking cigarettes to vaping were more likely to have initiated e-cigarette use
with non-tobacco flavors (Russell, McKeganey, Dickson, & Nides, 2018), and vapers who
persisted in e-cigarette use were more likely to use flavors other than tobacco or menthol
(Yingst, Foulds, Veldheer, & Du, 2018).
Strengths of the current study include the double-blind manipulation of flavor, inclusion
of e-cigarette-naïve chronic smokers, experimental inducement of nicotine withdrawal and use of
recent-generation e-cigarette devices. The experimental design allowed for a within-subjects
comparison of the effects of flavor, and the multi-level data set provided sufficient power to test
the main effects of the flavor manipulation and mediational analyses. Future research with larger
samples can test interactive effects and between-subjects moderators (e.g., race, gender). Given
that breath CO level significantly declined from the baseline to the experimental sessions, it is
likely participants experienced a period of tobacco abstinence that induced nicotine withdrawal
and cigarette craving. Since all of the participants were long-term combustible cigarette smokers
who had never previously used e-cigarettes, these results may generalize to treatment-seeking
chronic smoker populations.
Limitations of the study include the evaluation of only one sweet and tobacco flavor.
Given that we only assessed two flavorings (i.e., sweet and tobacco), the results should be
extended to the wide variety of e-cigarette flavorings currently available on the market (Zhu et
al., 2014) in order to determine the relative efficacy of sweet and tobacco flavors at reducing
64
motivation to reinstate smoking. The exclusion of all participants who smoked mentholated
combustible cigarettes may limit the generalizability of results, as smokers of non-mentholated
cigarettes may differ from smokers of mentholated cigarettes in their preferences for sweet-
flavored e-cigarettes. Additionally, the study sample was predominately composed of African-
American non-menthol smokers, a minority of African American smokers overall. We did not
collect blood during the study, and thus were unable to measure blood nicotine levels, however
we used a recent-generation device that is similar to commonly-used models that have been
shown to efficiently deliver nicotine (Wagener et al., 2017). Since the study took place in a
laboratory setting and utilized a standardized e-cigarette administration, it is unknown if the
findings extend to the natural ecology and more frequent patterns of use.

CONCLUSIONS
The net public health impact of e-cigarettes is currently unknown, as they may adversely
impact youth while also serving as a putative harm reduction tool for combustible cigarette
smokers. These preliminary results suggest that flavor may be an important e-cigarette product
characteristic to consider among smokers seeking to transition to lower harm products.
Additional data is needed to guide future regulatory decisions on the basis of whether flavored e-
cigarettes alter patterns of combustible cigarette smoking by suppressing motivation to reinstate
smoking. Innovative policies and strategies that protect youth while simultaneously promoting
smoking cessation among adults are needed to address the regulatory challenge of e-cigarettes.

65
Table 6. Sample Descriptive and Smoking Characteristics
Descriptive characteristics
N (%) or M (SD)
Sociodemographics

Female gender
12 (32.43)
Age 55.24 (7.56)
Race/Ethnicity
African-American 21 (56.76)
Hispanic 3 (8.11)
White 12 (32.43)
Other 1 (2.70)
Some College or More Education

21 (56.76)
Annual Income < $15,000 18 (48.65)
Smoking Characteristics
FTND 6.22 (1.89)
Number of cigarettes currently smoked/day 14.81 (6.27)
Baseline CO 14.95 (4.80)
Experimental CO 4.69 (1.98)
WISDM-PR 4.38 (2.27)
WISDM-NR 9.19 (3.84)
Age first smoke 1 cigarette/day 17.38 (7.81)
Age smoke everyday 19.24 (7.88)
Lifetime number of serious quit attempts 11.62 (24.15)
Intrapersonal Characteristics
AUDIT 3.73 (7.11)
DAST 2.81 (2.72)
STQ 42.78 (18.03)
Note. N=37. Abbreviations: FTND = Fagerström Test of Nicotine Dependence (Range 0-10); CO = Breath carbon
monoxide (ppm); WISDM = Wisconsin Inventory of Smoking Dependence Motives; PR = Positive reinforcement;
NR = Negative reinforcement; AUDIT = Alcohol Use Disorder Identification Test (Range: 0-40); DAST = Drug
Abuse Screening Test (Range: 0-10); STQ = Sweet Taste Questionnaire (Range: 7-84).

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Table 7. Vaping-Induced Satiation Effects by e-Cigarette Flavor Condition
Differences in Vaping-Induced Satiation Effect
Measure
Sweet Flavor Tobacco Flavor Contrast Effect Size
M (SE) M (SE) Difference (95% CI) Cohen’s d
Cigarette Craving
QSU-Total 25.35 (2.16) 24.41 (2.16) 0.95 (-3.06, 4.95) 0.07
QSU-Factor 1 16.65 (1.19) 15.84 (1.19) 0.81 (-1.73, 3.36) 0.11
QSU-Factor 2 8.70 (1.18) 8.57 (1.18) 0.14 (-1.74, 2.01) 0.02
TCQ-Emotionality 8.85 (0.48) 9.12 (0.48) -0.28 (-1.53, 0.98) -0.10
TCQ-Expectancy 14.34 (0.78) 13.79 (0.78) 0.55 (-1.03, 2.13) 0.12
TCQ-Compulsivity 8.67 (0.60) 8.76 (0.60) -0.09 (-1.35, 1.17) -0.02
TCQ-Purposefulness 11.86 (0.58) 11.54 (0.58) 0.32 (-1.02, 1.67) 0.09
WSWS-Craving 10.11 (0.64) 9.87 (0.64) 0.24 (-0.87, 1.36) 0.06
Nicotine Withdrawal
MNWS 14.92 (1.68) 14.27 (1.68) 0.65 (-2.27, 3.56) 0.06
WSWS-Sum 51.68 (2.22) 51.08 (2.22) 0.60 (-2.70, 3.89) 0.04
WSWS-Anger 4.08 (0.53) 4.46 (0.53) -0.38 (-1.42, 0.66) -0.12
WSWS-Anxiety 7.41 (0.44) 7.60 (0.43) -0.19 (-0.97, 0.59) -0.07
WSWS-Concentration 5.00 (0.36) 5.23 (0.36) -0.24 (-1.04, 0.55) -0.11
WSWS-Hunger 8.87 (0.64) 8.73 (0.64) 0.14 (-0.80, 1.07) 0.04
WSWS-Sadness 6.35 (0.28) 5.97 (0.28) 0.38 (-0.25, 1.01) 0.22
WSWS-Sleep 9.87 (0.39) 9.22 (0.39) 0.65 (-0.17, 1.47) 0.27
Positive Affect
PANAS-Positive Affect 28.61 (0.88) 27.31 (0.88) 1.31 (-0.67, 3.28) 0.24
POMS-Positive Mood 38.81 (2.87) 38.68 (2.87) 0.14 (-3.66, 3.93) 0.01
Negative Affect
PANAS-Negative Affect 12.36 (0.50) 12.20 (0.50) 0.16 (-1.04, 1.36) 0.05
POMS-Negative Mood 26.27 (3.58) 27.38 (3.58) -1.11 (-7.08, 4.86) -0.05
POMS-Total Mood Disturbance 17.62 (4.88) 19.27 (4.88) -1.65 (-9.72, 6.43) -0.06
SHAPS 2.54 (0.66) 3.70 (0.66) -1.16 (-2.38, 0.06) -0.29
Physiological Measures
Systolic BP 130.83 (1.18) 130.18 (1.18) 0.65 (-2.71, 4.01) 0.09
Diastolic BP 84.92 (1.70) 87.78 (1.70) -2.87 (-7.36, 1.63) -0.28
Heart rate 74.63 (0.87) 73.10 (0.87) 1.54 (-0.78, 3.85) 0.29

Note. N=37. Difference = Sweet – Tobacco. Abbreviations: QSU = Questionnaire of Smoking Urges; TCQ =
Tobacco Craving Questionnaire; MNWS = Minnesota Nicotine Withdrawal Scale; WSWS = Wisconsin Smoking
Withdrawal Scale; PANAS = Positive Affect Negative Affect Schedule; POMS = Profile of Mood States; SHAPS =
Snaith-Hamilton Pleasure Scale. BP = Blood pressure. QSU Factor 1 = Desire for the positive effects of smoking;
QSU Factor 2 = Desire for relief of negative affect.
*
p < 0.05.
67
Table 8. Mediation of the Effects of Flavor Condition (Sweet vs. Tobacco) on RAT Outcomes by Subjective Vaping Effects
Flavor condition à
Subjective Effect
Mediator
(A path)
Subjective Effect
Mediator à
BST Outcome
(B path)
Direct
Effect
Flavor à Subjective Effect
à RAT Outcome
(Indirect effect)
Total
Effect
(C Path)
Proportion of Effect Mediated
Smoking Delay
Appeal -18.32 -0.002 -10.66
**
0.04 -10.62
†
-0.004
Attractive Sensory Effects -17.11 -0.06 -11.57
**
0.95 -10.62
†
-0.09
Aversive Sensory Effects 12.66 0.01 -10.79
**
0.17 -10.62
†
-0.02
Psychological Reward -12.38 -0.15 -12.53
**
1.90 -10.62
†
-0.18
Smoking Behavior
Appeal -18.32 -0.004 0.55
**
0.07 0.62
†
0.12
Attractive Sensory Effects -17.11 -0.01 0.53
**
0.09 0.62
†
0.15
Aversive Sensory Effects 12.66 0.005 0.56
**
0.06 0.62
†
0.09
Psychological Reward -12.38 0.004 0.67
**
-0.05 0.62
†
-0.08
Note. N=37. Abbreviations: BST, Behavioral Smoking Task. Smoking Delay = Number of minutes delayed initiation of smoking. Smoking Behavior = Number
of cigarettes smoked during self-administration period.
*
p<.05;
**
p<.01;
†
p<.001.

68
Figure 4. Experimental Session Timeline

Note. Abbreviations: PANAS, Positive Affect Negative Affect Schedule; TCQ, Tobacco Craving Questionnaire; QSU, Questionnaire of Smoking Urges;
MNWS, Minnesota Nicotine Withdrawal Scale; WSWS, Wisconsin Smoking Withdrawal Scale; POMS, Profile of Mood States; SHAPS, Snaith-Hamilton
Pleasure Scale.
Pre-Ad. = Pre e-Cigarette Administration assessment (PANAS, TCQ). Post-Ad. = Post e-Cigarette Administration (PANAS, TCQ, QSU, MNWS, WSWS,
POMS, SHAPS. Pre-Rest = Pre Rest Period assessment; Post-Rest = Post Rest Period assessment. All assessments include subjective and physiological
measures.
Start of session
11:00 11:30 12:00 12:30 1:00 1:30 2:00 2:30 3:00
Pre-Ad.

Standardized
e-cigarette
administration
Post-Ad.

Smoking Delay Task
Rest Period
Pre-Rest

Post-Rest

69
Figure 5. Smoking Delay Task Outcomes by Flavor Condition

Note. N=37. *Significantly different than tobacco-flavor (p < 0.05). **Significantly different than tobacco-flavor (p
< 0.01).

**
0
10
20
30
40
50
Mintutes Delated Initiation of Smoking (±SE)
A
Sweet-Flavor
Tobacco-Flavor
*
0
1
2
3
4
5
6
7
8
Number of cigarettes smoked (M±SE)
B
Sweet-Flavor
Tobacco-Flavor
70
Figure 6. Effects of Flavor on Acute Subjective Vaping Effects

Note. N = 37. Appeal = Mean of “Like,” “Use Again,” and “Dislike” (reverse-scored). Attractive Sensory Effects = Mean of “Sweet,” “Smooth” and “Throat Hit
(Like)”. Aversive Sensory Effects = Mean of “Bitter,” and “Harsh”. Psychological reward = Mean of “Did it calm you down?”, “Did it help you concentrate?”,
“Did it make you feel more awake?”, “Did it reduce your hunger for food?”, Did it make you feel less irritable?”.
*Significantly different than tobacco (p<0.05); **Significantly different than tobacco (p<0.01). †Significantly different than tobacco (p<0.001).
**
†
**
**
0
10
20
30
40
50
60
70
80
90
100
Appeal Attractive Sensory Effects Aversive Sensory Effects Psychological Reward
Sweet
Tobacco
71
CHAPTER 4: GENDER DIFFERENCES IN THE APPEAL AND SENSORY EFFECTS
OF FLAVORED E-CIGARETTES AMONG YOUNG ADULT VAPERS

ABSTRACT

Background: The tobacco literature suggests that females (vs. males) may be more sensitive to
the sensory aspects of smoking (e.g., flavor, taste). Evidence from controlled laboratory research
demonstrates that flavored electronic cigarettes (e-cigarettes) are appealing due to their sensory
properties (e.g., sweetness, coolness). However, it is unknown if there are gender differences in
the appeal and sensory effects of flavored e-cigarettes. Methods: Young adult vapers (N=100;
35% Female; Mean Age=25.4; 53% smokers) attended one laboratory session in which they self-
administered 40 standardized e-cigarette doses according to a Flavor (sweet vs. tobacco vs.
menthol vs. flavorless) × Nicotine (6 mg/mL vs. 0 mg/mL) × Voltage (3.3V vs. 4.3V) factorial
design. Following each trial, participants completed ratings of appeal (liking, disliking,
willingness-to-use-again), attractive sensory effects (sweetness, smoothness, throat hit appeal),
and aversive sensory effects (bitterness, harshness). Gender was tested as a between-subjects
moderator of all composite outcomes (i.e., appeal, attractive sensory effects, aversive sensory
effects) in separate multilevel linear models. Results: There were significant interactions
between gender and flavor for the appeal (p<0.001) and attractive sensory effects outcomes
(p=0.001), but not aversive sensory effects (p=0.15). Males preferred sweet-flavored e-cigarettes
to the menthol, tobacco and flavorless conditions (ps<0.001), whereas there were no significant
differences in the appeal of menthol- and sweet-flavored e-cigarettes among females (p=0.40),
which were both more appealing than the tobacco and flavorless conditions (ps<0.05).
Conclusions: Menthol-flavored e-cigarettes may be uniquely appealing to female vapers.
Understanding the appeal of flavored e-cigarettes in both genders can inform e-cigarette
72
prevention efforts among youth as well as determining if flavored noncombustible tobacco
products may have some utility as reduced harm products among adult smokers.
73
INTRODUCTION
Combustible cigarettes are rewarding due to their pharmacological (i.e., nicotine-related)
and non-pharmacological properties, including their sensory effects (Chaudhri et al., 2006; Rose,
2006; Rose et al., 2010). Evidence suggests that female smokers may be more strongly
influenced by the sensory (e.g., flavor, taste) aspects of smoking than males (Perkins et al., 2001;
Perkins et al., 2002). Females smokers (vs. males) rate cigarettes as less appealing and
reinforcing when the olfactory and taste stimuli of cigarettes are blocked (Perkins et al., 2001),
and experience significantly greater relief from nicotine withdrawal after smoking reduced
nicotine or completely denicotinized cigarettes (Barrett, 2010; Faulkner et al., 2018; Perkins &
Karelitz, 2015). Internal tobacco industry documents reveal that female smokers are more likely
than males to smoke flavored cigarettes, and that manufacturers have designed products to
appeal to female smokers’ preference for smooth and mild taste sensations (Carpenter et al.,
2005).
In contrast, males may be more sensitive to the pharmacological and rewarding effects of
nicotine. Tobacco company documents and internal studies note that the rewarding effects of
nicotine are a primary reason for smoking among males (Carpenter et al., 2005). Male smokers
(vs. females) report greater changes in the reinforcing effects of cigarettes and experience greater
relief of nicotine withdrawal symptoms (e.g., negative affect) after smoking cigarettes with
nicotine compared to a denicotinized cigarette (Perkins et al., 2002; Perkins & Karelitz, 2015).
The addition of characterizing flavors (e.g., fruit, chocolate, menthol) enhances the
appeal of combustible cigarettes by improving their palatability and masking the bitterness and
harshness produced by nicotine and the combustion of tobacco (Brown, Luo, Isabelle, &
Pankow, 2014; Feirman et al., 2015). To protect youth from flavored tobacco products, the 2009
74
Family Smoking Prevention and Tobacco Control Act prohibited the addition of characterizing
flavors (e.g., candy, fruit) other than menthol in combustible cigarettes (Food & Drug
Administration, 2010). However, these limitations do not apply to new alternative tobacco
products, such as electronic cigarettes (e-cigarettes), which are currently available in a wide
variety of flavorings that are popular among youth and young adults (Schoenborn & Gindi, 2015;
Singh, 2016). The Food and Drug Administration’s (FDA) 2016 Deeming Rule provided its
Center for Tobacco Products (CTP) with the authority to regulate e-cigarettes as tobacco
products, however the Deeming Rule did not prohibit flavored e-cigarettes, despite the existing
ban on flavored combustible cigarettes (Food & Drug Administration, 2016).
Controlled laboratory research demonstrates that flavored e-cigarettes are more appealing
than unflavored e-cigarettes (i.e., tobacco-flavored and flavorless), largely due to their attractive
sensory properties (Audrain-McGovern et al., 2016; Goldenson et al., 2016; Kim et al., 2016;
Litt et al., 2016; Rosbrook & Green, 2016). Sweet-flavored e-cigarettes (vs. non-sweet) have
been shown to enhance the perceived sweetness of e-cigarettes (Audrain-McGovern et al., 2016;
Goldenson et al., 2016; Kim et al., 2016), and menthol-flavored e-cigarettes increase coolness
and reduce airway irritation caused by the harshness of nicotine (Krishnan-Sarin et al., 2017; Litt
et al., 2016; Rosbrook & Green, 2016). Qualitative surveys and interviews suggests that females
may prefer flavored e-cigarettes (Dawkins, Turner, Roberts, & Soar, 2013; Kistler et al., 2017;
Piñeiro et al., 2016), however, few controlled studies have assessed gender differences in the
appeal and sensory effects of flavored e-cigarettes.
To determine the public health impact of flavored e-cigarettes it is necessary to consider
the risks and benefits posed to distinct segments of the population, including differences between
males and females. Given the combustible cigarette literature, it is possible that female e-
75
cigarette users may be more sensitive to the effects of flavorings in e-cigarettes. In this
controlled laboratory experiment, we tested the hypothesis that female e-cigarette users (vs.
males) would find flavored e-cigarettes more appealing and would be more sensitive to their
sensory effects. Based on the combustible cigarette and e-cigarette literatures, we also
hypothesize that nicotine may enhance the appeal and attractive sensory effects of e-cigarettes
more strongly in males (vs. females).

METHODS
Participants
Young adult e-cigarette users (N=100) were recruited in Los Angeles, CA in 2015 via
physical (i.e., flyers, bus) and online advertisements. Inclusion criteria were: (1) 18-35 years of
age; (2) e-cigarette use ≥1 day/week for ≥1 month; and (3) English fluency. Exclusion criteria
included: (1) desire to immediately reduce e-cigarette use; (2) smoking cessation medication use;
and (3) pregnancy or breastfeeding. All participants provided written informed consent and the
University of Southern California Institutional Review Board approved the study protocol.

Design
Following eligibility confirmation via telephone, participants attended a single four-hour
laboratory session in which they self-administered 40 different e-cigarette conditions that were
separated into four blocks of ten administrations. The 40 e-cigarette administrations were varied
according to a Flavor (5 sweet vs. 2 menthol vs. 2 tobacco vs. 1 flavorless) × Nicotine (6 mg/mL
vs. 0 mg/mL) × Voltage (3.3 V vs. 4.3 V) fully randomized within-participant factorial design.
76
A 30-minute rest period separated each block, during which participants completed
questionnaires.

Procedure
Participants were instructed to deprive themselves of all nicotine products (e.g., e-
cigarettes, combustible cigarettes) for two-hours before attending the laboratory session, and
completed carbon monoxide (CO; a biomarker for combustible tobacco exposure) and salivary
cotinine assessments (i.e., a biomarker for all nicotine exposure) before beginning the vaping
evaluation portion of the experiment. During each administration, an animated video cued
participants to inhale and exhale two times from the e-cigarette device according to a schedule
designed to approximate typical e-cigarette use patterns (Helen et al., 2016; Yip & Talbot, 2013).

Each administration was separated by a one-minute rest period in which participants were
prompted to drink water to prevent conflating prior administrations. In the 30-minute rest period
separating each block, participants completed surveys assessing demographics, health
information and e-cigarette and combustible cigarette use characteristics.

Materials
E-cigarette solutions were loaded into Joyetech “Delta 23 Atomizer” tanks that were
connected to a Joyetech “eVic Supreme” battery (i.e., a tank device) with atomizer resistance of
1.5Ω (Ohms). All e-cigarette solutions (Dekang Biotechnology Co., Ltd.) were composed of
50/50 propylene glycol/vegetable glycerin; nicotine concentration was either 6 mg/mL or 0
mg/mL. The 10 flavorings included 5 sweet-flavored solutions (i.e., blueberry, strawberry,
peach, watermelon, blackberry), 2 tobacco-flavored solutions (i.e., red USA, desert ship), 2
77
menthol solutions (i.e., triple menthol, portal blend) and a single flavorless solution. Device
voltage was set to 3.3V or 4.3V for each administration, resulting in wattages of 7.26 W and
12.33 W, respectively.

Measures
Outcome measures
After each 2-puff administration, participants answered three questions that assessed the
appeal of the preceding e-cigarette condition: (1) “How much did you like it?”; (2) “How much
did you dislike it?”; and (3) “Would you use it again?”. Participants also answered three
questions that assessed the attractive sensory effects: (1) “How sweet was it”; (2) “How smooth
was it?”; and (3) “How much did you like the throat hit?” and two questions that assessed the
aversive sensory effects: (1) “How harsh was it?”; and (2) “How bitter was it?”. All questions
were rated on visual analogue scales (VAS) from 0-100 with anchors of “Not at all” to
“Extremely”—with the exception of willingness-to-use-again, which used anchors of “Not at all”
to “Definitely.” The appeal and sensory effects measures were reduced to form 3 composite
measures (Song et al., 2013): (1) Appeal was the mean of “Liking,” “Willingness to use again,”
and “Disliking” (reverse-scored); (2) Attractive Sensory Effects was the mean of “Sweetness,”
“Smoothness,” and “Throat Hit appeal”; and (3) Aversive Sensory Effects was the mean of
“Bitterness” and “Harshness.”

Participant Characteristics
All participants completed investigator-created questionnaires that assessed
demographics, e-cigarette use characteristics (e.g., typical use patterns, device type, preferred
78
flavor, nicotine concentration) and the Penn State Electronic Cigarette Dependence Index
(PSECD; Foulds et al., 2015), a 10-item measure of current e-cigarette dependence (range: 0-20).
Participants also reported their preferred e-cigarette flavor, selecting their top choice from a list
of six options (i.e., fruit, candy, chocolate or other sweets, menthol, mint, tobacco): four separate
binary variables were created to operationalize preference for sweet, menthol/mint, tobacco and
flavorless e-cigarettes, respectively (yes/no). E-cigarette device type (i.e., first-, second- or third-
generation) was coded by model type according to commonly accepted nomenclature
(Barrington-Trimis et al., 2017). Participants who reported smoking more than 100 cigarettes in
their lifetime (N=78) were administered the Smoking History Questionnaire (Brown et al., 2002)
and the Fagerström Test of Cigarette dependence (FTCD; Heatherton et al., 1991), a well-
validated 6-item measure of combustible cigarette dependence (range: 0–10).

Data Analysis
Preliminary analyses calculated descriptive statistics for all demographic and smoking
and vaping characteristics, stratified by gender. Chi-squared and independent samples t-tests
assessed differences by gender. Fixed effects of flavor (i.e., sweet vs. menthol vs. tobacco vs.
flavorless), nicotine (i.e., nicotine vs. placebo), voltage (3.3 V vs. 4.3 V) and gender (male vs.
female) were included in multilevel linear (mixed) models with the three composite outcomes
(i.e., appeal, attractive sensory effects and aversive sensory effects) serving as dependent
variables in a series of separate models.
Gender was tested as a between-subjects moderator (i.e., interaction terms were created
for the gender × flavor, gender × nicotine and gender × voltage interactions) of all main effects
for the three composite outcomes in separate models. The three-way gender × flavor × nicotine
79
and gender × flavor × voltage interactions, including all two-way interaction terms, were also
tested in subsequent models. Participant characteristics that significantly differed by gender (i.e.,
race/ethnicity, e-cigarette dependence, preference for menthol-flavored e-cigarettes) or have
been shown to influence e-cigarette appeal (i.e., device type, preference for sweet flavorings)
(Shang et al., 2017) were included as covariates in all models (Table 9). Post-hoc pairwise tests
assessed differences in the composite outcomes between flavor (i.e., sweet vs. tobacco, sweet vs.
flavorless, sweet vs. menthol) and nicotine (i.e., nicotine vs. placebo) conditions within males
and females. Data were analyzed using IBM SPSS Statistics Version 24 with alpha set to 0.05
(IBM Corp., Armonk, NY).

RESULTS

Sample Characteristics
Thirty-five percent of participants were female, and slightly more than half of the sample
were current combustible cigarette smokers (53%; Table 9). Females (vs. males) reported, on
average, greater e-cigarette dependence on the PSECD (Foulds et al., 2015) (p=0.03), and a
significantly larger proportion of females (20%) than males (6.2%) reported a baseline
preference for menthol-flavored e-cigarettes (p=0.04). There were also significant differences in
the racial/ethnic distribution of males and females (p <0.001; Table 9).

Gender × Flavor Interactions
There were significant interactions between gender and flavor condition (i.e., variation in
the magnitude of differences in ratings among e-cigarette flavor conditions between males and
80
females) for the composite appeal (p < 0.001) and attractive sensory effects outcomes (p =
0.001), after controlling for baseline preference for menthol-flavored e-cigarettes and other
covariates (Table 10). There was not a significant interaction between gender and flavor
condition for the aversive sensory effects outcome (p = 0.15; Table 10).

Gender Differences in the Appeal of Flavored e-Cigarettes
Males rated the sweet-flavored e-cigarettes as significantly more appealing than the
menthol, tobacco and flavorless conditions, aggregated across the nicotine and voltage
conditions (Figure 7; ps <0.001). However, among females, menthol-flavored e-cigarettes were
rated as non-significantly more appealing than the sweet-flavored e-cigarettes (p = 0.40), and
sweet- and menthol-flavored e-cigarettes were both rated as more appealing than the tobacco and
flavorless conditions (ps <0.001). In direct comparisons by gender, females rated the menthol-
flavored e-cigarettes as more appealing than males at a level approaching statistical significance
(p=0.08), and males rated the flavorless e-cigarettes as non-significantly more appealing than
females (p=0.07; Figure 7).

Gender Differences in the Attractive Sensory Effects of Flavored e-Cigarettes
Males and females both rated the sweet-flavored e-cigarette condition as possessing
significantly greater attractive sensory effects than the three other flavor conditions (p < 0.004).
Females rated the menthol-flavored e-cigarettes as possessing significantly more attractive
sensory effects than tobacco and flavorless e-cigarette conditions (ps <0.001). Among males
there were no significant differences among the menthol and flavorless conditions (p = 0.48;
Figure 8), and menthol was rated as possessing significantly more attractive sensory effects than
81
tobacco (p = 0.003). In direct comparisons by flavor condition, males rated the attractive sensory
effects of the flavorless e-cigarette higher than females, but this did not reach statistical
significance (p = 0.06). Female’s preference for the attractive sensory effects of the menthol-
flavored e-cigarettes (vs. males) was also not statistically significant (p = 0.16; Figure 8).

Gender × Nicotine and Gender × Voltage Interactions
There were no significant two-way interactions between gender and nicotine for any of
the outcomes (ps > 0.67). The gender × voltage interaction for the appeal outcome approached
statistical significance (p = 0.08), with females displaying a greater difference between the high
and low voltage conditions (Difference [high–low] M [95% CI] = 11.43 [8.72, 14.14]) than
males (Difference [high–low] M [95% CI] = 8.45 [6.47, 10.44]). There were no statistically
significant gender × voltage interactions for either of the sensory effect outcomes (ps = 0.50 –
0.71). Additionally, there were no significant three-way interactions between gender, nicotine
and flavor (ps > 0.51), or gender, flavor and voltage (ps > 0.77) for any of the outcomes (Table
10).

DISCUSSION
In this laboratory study we found significant gender differences in the appeal and attractive
sensory effects of flavored e-cigarettes among young adult vapers. All participants rated sweet
and menthol-flavored e-cigarettes as more appealing than tobacco-flavored e-cigarettes, however
male vapers expressed a preference for sweet-flavored e-cigarettes, whereas female vapers rated
menthol-flavored e-cigarettes as more appealing. Data on the appeal and attractive sensory
effects of flavored e-cigarettes has important implications for two dimensions of public health
82
that fall under the FDA’s regulatory purview: (1) the growing popularity of flavored e-cigarettes
among non-smoking youth; and (2) encouraging the innovation of less harmful nicotine delivery
products that may aid adult combustible cigarette smokers in smoking reduction and cessation.
Female youth and young adults may be particularly vulnerable to the attractive sensory
effects of flavored e-cigarettes, which could maintain e-cigarette use and possibly lead to
transitions to combustible tobacco products (Carpenter et al., 2005; Hoffman et al., 2016;
Kostygina et al., 2014; Villanti et al., 2017). Recent evidence suggests that use of flavored e-
cigarettes may be related to persistent e-cigarette use among youth (Bold et al., 2016), as well as
increased frequency of past 30-day e-cigarette use (Morean et al., 2018). Furthermore, use of
flavored e-cigarettes (vs. unflavored) is associated with increased susceptibility to combustible
cigarette smoking among nonsmoking youth (Chen et al., 2017) and a reduced likelihood of
intentions to quit smoking among adolescent smokers (Dai & Hao, 2016). Thus, the availability
of flavored e-cigarettes may adversely impact the health of female youth who historically have
been targeted with flavored tobacco products (Carpenter et al., 2005).
Despite these risks to youth, the use of reduced-harm tobacco products could potentially
aid treatment-resistant adult female smokers in cessation efforts. Traditional nicotine
replacement therapies (NRT; e.g., nicotine patch and gum) are less effective in female (vs. male)
smokers, who display lower quit rates and maintain fewer long-term treatment gains (Cepeda-
Benito et al., 2004; Perkins & Scott, 2008). Novel treatments that incorporate appealing sensory
effects may be efficacious among female smokers. In a smoking reduction trial using flavored e-
cigarettes, menthol-flavored e-cigarettes (vs. tobacco-flavored e-cigarettes) resulted in the largest
gains in smoking reduction among all smokers (Litt et al., 2016).
Women are vulnerable to unique health problems from combustible tobacco, such as
83
breast cancer (Prescott et al., 1998). Identifying flavorings that are appealing to females could
allow for gender-specific treatments that increase the adoption of e-cigarettes among female
smokers who have difficulty quitting smoking with currently available treatments (Perkins, 2001;
Wetter et al., 1999). However, it is important to note that e-cigarettes are not currently classified
as therapeutic drug devices by the FDA, and no randomized controlled trials to date supports the
efficacy of e-cigarettes as smoking cessation treatment (Kalkhoran & Glantz, 2016; Khoudigian
et al., 2016). While offering promise, more research is needed before it can be concluded that
flavored e-cigarettes may aid female smokers in cessation efforts.
The combustible cigarette and e-cigarette literatures indicate that menthol may be a
particularly important e-cigarette flavoring to consider among females. Menthol attenuates the
activation of the nicotinic-acetylcholine system, inhibiting the metabolism of nicotine (Ashoor et
al., 2013; Benowitz, Herrera, & Jacob, 2004; Hans, Wilhelm, & Swandulla, 2012) and increasing
the threshold for perceiving the effects of nicotine (DeVito, Valentine, Herman, Jensen, &
Sofuoglu, 2016; Perkins, Kunkle, & Karelitz, 2017). Preclinical evidence suggests that female
smokers may have a genetic preference for the analgesic effects of menthol, possibly as a result
of TAS2R38 taste receptor gene and a propensity to experience bitter taste sensations (Oncken et
al., 2015). Additionally, epidemiological data indicates that a greater proportion of females (vs.
males) smoke menthol cigarettes (Cubbin, Soobader, & LeClere, 2010; Rath et al., 2016; Sidney,
Tekawa, & Friedman, 1989), and in this study a greater proportion of females (vs. males)
reported a baseline preference for menthol-flavored e-cigarettes.
The finding that female vapers prefer menthol concords with and extends preliminary
evidence from laboratory studies regarding gender differences in the effects of menthol-flavored
e-cigarettes. An experiment that tested the effects of varying levels of nicotine and menthol
84
concentrations on appeal found a three-way interaction between menthol, nicotine content and
gender, with females (vs. males) preferring menthol-flavoring in the absence of nicotine and
reporting stronger sensory effects at lower menthol concentrations (Rosbrook & Green, 2016).
In another study of non-treatment seeking smokers, females (vs. males) vaped less when
presented with their non-preferred flavor (i.e., tobacco vs. menthol) and rated their non-preferred
e-cigarette flavor as less rewarding (Oncken et al., 2015). Given this data, additional research is
needed to determine the overall public health impact of menthol-flavored e-cigarettes among
females.
While we did not find a significant interaction between gender and nicotine content, there
are several factors that could explain the lack of gender differences in the effects of nicotine.
Participants self-administered only one active dose of nicotine (i.e., 6 mg/mL), considered low-
to-medium strength given the device and wattage used, and it is possible that the nicotine dose
was not sufficient to impact appeal and the sensory effects. Additionally, participants were only
required to abstain from tobacco products for two hours before the experimental session and may
have been nicotine-sated. Furthermore, since we assessed only the acute effects of nicotine with
self-report measures, we likely did not capture the longer-term pharmacological effects of
nicotine. Finally, the method of nicotine administration and impact of hormones and ovarian
cycle in female participants have been shown to alter the effects of nicotine (Goletiani, Siegel,
Lukas, & Hudson, 2015; Perkins, 1999; Sofuoglu, Mitchell, & Mooney, 2009), and should be
accounted for in future research.
Strengths of the study include the relatively large and demographically diverse sample,
multivariate data structure and manipulation of several key product characteristics (i.e., flavor,
nicotine and device voltage) in a controlled laboratory setting. The sample size was sufficient to
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test interactions with between-participant user characteristics and identify sources of
heterogeneity in the effects of flavored e-cigarettes. Additionally, participants were relatively
evenly distributed by smoking status, as the sample included never-smokers, former smokers
who currently vape, as well as current smokers and vapers (dual-users). Future research
examining gender differences in the effects of flavored e-cigarettes in specific segments of the
population (e.g., adult smokers and non-smoking youth) can further elucidate the overall public
health impact of flavored e-cigarettes.
Limitations include the evaluation of only acute dimensions of appeal, and use of self-
report measures. Future research should also assess more diverse outcomes (e.g., self-
administration and physiological effects) indicative of long-term appeal. The fully-randomized
design allowed us to largely eliminate order effects, but may have conflated some of the
administrations and made it difficult to assess the pharmacological effects of nicotine. The
study’s sample did not contain adult smokers over the age of 35 or e-cigarette-naïve smokers,
and the results of this study should be extended to adult smokers who have not previously used
e-cigarettes in order to determine the ability of flavored e-cigarettes to potentially serve as harm
reduction aids in this population.
CONCLUSIONS
In this controlled study laboratory experiment we found significant gender differences in
the appeal and attractive sensory effects of flavored e-cigarettes among young adult vapers, with
females expressing a preference for menthol-flavored e-cigarettes. Flavored e-cigarettes may
differentially impact females, and this study reinforces the need for researchers to include
females participants in laboratory and clinical studies. Assessing moderators of product appeal
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can inform interventions focused on youth e-cigarette prevention as well as smoking reduction
and cessation treatments among adult smokers, informing effective regulatory policy regarding
the availability of flavored e-cigarettes.

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Table 9. Sample Descriptive Characteristics by Gender

Demographic Characteristics Total (N=100) Male (N=65) Female (N=35) Difference (p)
Age (years), M (SD) 25.4 (4.4) 25.3 (4.5) 25.6 (4.3) 0.77
Race/Ethnicity <0.001
Hispanic 22 (22.0%) 16 (24.6%) 6 (17.1%)
White 29 (29.0%) 15 (23.1%) 14 (40.0%)
Black 26 (26.0%) 18 (27.7%) 8 (22.9%)
Asian 14 (14.0%) 9 (13.8%) 5 (14.3%)
Other 9 (9.0%) 7 (10.8%) 2 (5.7%)
Smoking Characteristics
Smoking Status 0.68
Never-Smoker 22 (22.0%) 16 (24.6%) 6 (17.1%)
Past Smoker 25 (25.0%) 16 (24.6%) 9 (25.7%)
Current Smoker 53 (53.0%) 33 (50.8%) 20 (57.2%)
Smoke(d) Menthol Cigarettes 33 (33.0%) 20 (30.8%) 13 (37.1%) 0.51
Carbon monoxide,
a
M (SD) 5.0 (5.5) 5.4 (5.9) 4.2 (4.5) 0.29
Salivary cotinine,
b
M (SD) 2.8 (1.2) 2.8 (1.4) 2.9 (0.9) 0.69
Age Smoke 1 cig/day, M (SD) 18.2 (9.0) 19.5 (10.5) 15.9 (4.3) 0.15
FTCD,
c
M (SD) 2.5 (1.9) 2.3 (1.9) 2.8 (1.9) 0.36
Vaping Characteristics
PSECD,
d
M (SD) 7.7 (4.8) 7.0 (4.5) 9.1 (4.9) 0.03
Puffs per day, M (SD) 74.3 (123.7) 72.5 (94.9) 77.6 (164.3) 0.85
Nicotine Concentration, M (SD) 7.2 (7.6) 6.5 (5.3) 8.5 (10.6) 0.22
Age vape everyday, M (SD) 22.8 (4.5) 22.6 (4.4) 23.1 (4.7) 0.60
e-Cigarette Device Type 0.47
1
st
Generation Device 12 (12.0%) 6 (9.2%) 6 (17.1%)
2
nd
Generation Device 30 (30.0%) 21 (32.3%) 9 (25.7%)
3
rd
Generation Device 58 (58.0%) 38 (58.5%) 20 (57.1%)
e-Cigarette Flavor Preference
Prefer Sweet (yes/no) 80 (80.0%) 55 (84.6%) 25 (71.4%) 0.11
Prefer Menthol (yes/no) 11 (11.0%) 4 (6.2%) 7 (20%) 0.04
Prefer Tobacco (yes/no) 6 (6.0%) 4 (6.2%) 2 (5.7%) 0.58

Note. N=100. Data presented as N (%) unless otherwise noted. Difference = tests of differences in sample
characteristics between males and females with values from either c
2
(categorical variables) or independent samples
t-tests (continuous variables).
a
End-tidal carbon monoxide (ppm).

b
NicAlert semi-quantitative cotinine strip (range 1–6).
c
Fagerström Test of Cigarette Dependence (range 0-10) with higher scores indicating greater dependence.
d
Penn. State Electronic Cigarette Dependence Index (range 0-20) with higher scores indicating greater dependence.

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Table 10. Two-way and Three-way Interactions of Gender, Flavor and Nicotine

Outcome 2-Way Interactions 3-Way Interactions
Flavor×Gender Nicotine×Gender Voltage×Gender Flavor×Nicotine×Gender Flavor×Voltage×Gender
Appeal 8.06
†
0.97 3.01 0.78 0.38
Attractive Sensory Effects 5.53
**
0.64 0.64 0.77 0.02
Aversive Sensory Effects 1.79 0.13 0.14 0.97 0.35

Note. N = 100 (35 female). All values are reported as F statistics from multilevel linear models.
Adjusted for race/ethnicity, e-cigarette dependence and preference for menthol-flavored e-cigarettes.
Appeal = Mean of “Like” and “Use Again” and “Dislike” (reverse-scored).
Attractive Sensory Effects = Mean of “Sweet” and “Smooth” and “Throat Hit Appeal.”
Aversive Sensory Effects = Mean of “Harsh” and “Bitter”.
*p<0.05; **p<0.01; †p<0.001.

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Figure 7. Gender Differences in the Appeal of Flavored e-Cigarettes

Note. N = 100 (35 female).
Adjusted for race/ethnicity, e-cigarette dependence, e-cigarette device type, baseline preference for menthol-
flavored e-cigarettes and baseline preference for sweet-flavored e-cigarettes.
Appeal = Mean of “Like,” “Use Again” and “Dislike” (reverse-scored).
†Significantly greater than flavorless (p<0.01); *Significantly greater than tobacco (p<0.01); ÑSignificantly greater
than menthol (p<0.01).

*†Ñ
*†
*
*†
0
20
40
60
80
100
Male Female
Appeal
Sweet Tobacco
Flavorless Menthol
90
Figure 8. Gender Differences in the Attractive Sensory Effects of Flavored e-Cigarettes

Note. N = 100 (35 female).
Adjusted for race/ethnicity, e-cigarette dependence, e-cigarette device type, baseline preference for menthol-
flavored e-cigarettes and baseline preference for sweet-flavored e-cigarettes.
Attractive Sensory Effects = Mean of “Sweet,” “Smooth” and “Throat Hit (Like)”.
†Significantly greater than flavorless (p<0.01); *Significantly greater than tobacco (p<0.01); ÑSignificantly greater
than menthol (p<0.01).

*†Ñ
*†Ñ
*
*†
0
20
40
60
80
100
Male Female
Attractive Sensory Effects
Sweet Tobacco
Flavorless Menthol
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CHAPTER 5: DISCUSSION AND CONCLUSIONS

The ongoing availability of flavored e-cigarettes constitutes a unique regulatory
challenge, as evidence suggests e-cigarettes could both harm and potentially benefit net
population health. There exists a need for evidence-based regulatory policies that prevent a new
generation of youth from becoming addicted to nicotine while also decreasing smoking rates and
the resultant morbidity and mortality among adult smokers. This dissertation extends the extant
evidence on the public health impact of flavored e-cigarettes by integrating multiple streams of
data regarding the effects of flavored e-cigarettes. The three independent studies included in this
dissertation assessed the effects of flavored e-cigarettes in three populations of interest to the
current regulatory debate: (1) adolescent e-cigarette users; (2) adult smokers; and (3) young adult
e-cigarette users. Each of the three studies utilized distinct data sets and methodologies to
determine if: (1) the use of sweet-flavored e-cigarettes by adolescent vapers was prospectively
associated with persistent e-cigarette and subsequent combustible cigarette smoking across a
two-year period; (2) the administration of sweet-flavored e-cigarettes (vs. tobacco-flavored)
suppressed motivation to reinstate smoking and nicotine withdrawal symptoms among adult
combustible cigarette smokers during tobacco abstinence; and (3) the appeal and sensory effects
of flavored e-cigarettes differ between male and female young adult e-cigarette users.
To answer these questions the first study (Chapter 2) followed a cohort of over 3,000
high school students across their last two years of high school to determine if use of sweet-
flavored e-cigarettes predicted subsequent past 6-month and past 30-day e-cigarette and
combustible cigarette use. Chapter 3 of this dissertation detailed the findings of a laboratory
experiment in which e-cigarette flavor (sweet vs. tobacco) was experimentally manipulated
among a sample of adult smokers who had never previously used e-cigarettes to determine if e-
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cigarette flavor could reduce smoking reinstatement behavior and self-reported nicotine
withdrawal symptoms. In the third study (Chapter 4), young adult e-cigarette users attended a
single laboratory session in which they sampled and rated the appeal and sensory qualities of
four different flavored e-cigarettes (i.e., sweet, menthol, tobacco, flavorless) as part of a
controlled administration procedure. Together, these three studies contribute novel data
regarding both the acute and long-term effects of flavored e-cigarettes among adolescents, young
adults and adult smokers, informing both sides of the public health and regulatory debate.
Research demonstrates that while a substantial proportion of adolescents experiment with
e-cigarettes, only a portion of these youth become regular vapers following initiation (Health &
Services, 2016). Hence, it is particularly important to identify factors that may sustain vaping
following initiation during adolescence. To determine the impact of sweet-flavored e-cigarettes
on persistent e-cigarette use over a two-year period, students from ten high schools in the Los
Angeles metropolitan area completed a total of five bi-annual surveys beginning at the end of
their second year (spring 2015) through the end of their fourth year of high school (spring 2017).
Students who used sweet-flavored e-cigarettes (vs. those who exclusively used non-sweet-
flavored [i.e., tobacco, menthol or flavorless] e-cigarettes) at the first four assessments were
more likely to persist in e-cigarette use (i.e., report past 6-month and past 30-day e-cigarette use)
at the subsequent 6-month follow-up assessment across the study period. These associations
remained statistically significant after adjustment for demographic covariates, frequency of past
30-day vaping and smoking and e-cigarette nicotine concentration, suggesting that flavor may
play a unique role in maintaining vaping behavior. Additionally, use of a greater number of total
e-cigarette flavorings was associated with increased likelihood of persistent vaping.
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These results extend the extant observational research on adolescent flavored e-cigarette
use—that has primarily consisted of cross-sectional surveys or studies with one follow-up time
point—by examining associations between sweet-flavored e-cigarette use and tobacco product
use over a two-year period. This new finding raises concern that flavored e-cigarettes may be
contributing to a class of tobacco product users who maintain vaping throughout adolescence,
rather than just experimenting with e-cigarettes. There was not a significant association between
sweet-flavored e-cigarette use and subsequent combustible cigarette smoking, however this null
finding may be explained by low rates of smoking in this sample or differences in flavored e-
cigarette use by smoking status, and should be further explored in future research. Research is
also needed to determine the effect of e-cigarette flavor on developmental patterns of tobacco
product use and nicotine dependence.
The second study included in this dissertation (“Effects of Sweet-Flavored e-Cigarettes
on Smoking Reinstatement in Nicotine-Deprived Smokers”) was designed as a controlled test of
the ability of sweet-flavored e-cigarettes to reduce smoking reinstatement behavior and nicotine
withdrawal symptoms among adult combustible cigarette smokers who were deprived of tobacco
products overnight and experiencing nicotine withdrawal. While previous laboratory research
has examined the appeal of flavored e-cigarettes among young adult and adult vapers
(Goldenson et al., 2016; Kim et al., 2016) and quasi-experimental trials have assessed their
utility as smoking reduction aids among adult smokers (Litt et al., 2016), no controlled within-
subjects study has isolated the effects of flavor on motivation to reinstate smoking and nicotine
withdrawal symptoms. Findings from this study suggest that sweet-flavored (vs. tobacco-
flavored) e-cigarettes may reduce motivation to reinstate smoking after overnight tobacco
abstinence, as participants were more likely to delay smoking and smoke fewer cigarettes during
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the session they self-administered the sweet-flavored (vs. tobacco-flavored) e-cigarette. These
results may inform the development of noncombustible nicotine-delivery products that could aid
smoking reduction and cessation treatment among long-term treatment-resistant adult smokers
who continue to need or want nicotine. However, when interpreting the public health
significance of the results detailed in this study there are several important qualifying factors to
consider, including the lack of a reduction in subjective nicotine withdrawal symptoms.
Despite the significant effects of sweet-flavor on two aspects of motivation to reinstate
smoking, there were no significant differences in subjective (self-reported) nicotine withdrawal
symptoms between the sweet- and tobacco-flavored e-cigarette conditions. The ability of
nicotine replacement products to reduce withdrawal symptoms during tobacco abstinence is a
key feature that is essential for aiding smoking cessation. Thus, it may be premature to conclude
that sweet-flavored e-cigarettes could benefit adult smokers. However, tobacco dependence is a
complex neurobehavioral process that involves both psychological and physical withdrawal
symptoms. Although we used validated self-report measures of nicotine withdrawal, they may
not have captured the underlying behavioral motivation to reinstate smoking that varied by e-
cigarette flavor. Taken together, the results emphasize the importance of considering subjective
and behavioral outcomes in future behavioral pharmacology research studies.
The second laboratory study included in this dissertation, “Gender Differences in the
Appeal and Sensory Effects of Flavored e-Cigarettes among Young Adult Vapers” (Chapter 4)
found significant gender differences in the appeal and positive sensory effects of flavored e-
cigarettes, with female participants expressing a preference for menthol-flavored e-cigarettes.
These results concord with the extant literature demonstrating that female smokers are more
sensitive to the sensory effects of combustible cigarettes, as well as more recent research that has
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identified gender differences in the effects of menthol-flavored e-cigarettes (Oncken et al., 2015;
Rosbrook & Green, 2016). This study extends prior research by directly comparing the effects
of sweet- and menthol-flavored e-cigarettes, with tobacco and flavorless solutions serving as
active control conditions. The findings of this study suggest that while sweet-flavored e-
cigarettes appear to be universally appealing (i.e., appealing to both men and women), female
vapers (vs. male) may be particularly sensitive to the effects of menthol.
These results could have important implications for youth e-cigarette prevention
programs as well as the development of gender-targeted smoking cessation and reduction
treatment among adult smokers. Research suggests that menthol’s ability to reduce the aversive
sensations of combustible tobacco products may facilitate continued experimentation among
youth (Anderson, 2011; D’Silva, Cohn, Johnson, & Villanti, 2017). As menthol is the only
characterizing flavor currently allowed in combustible cigarettes it occupies a unique position in
the regulatory domain. Given the abovementioned results from laboratory studies and
observational research, research is needed to gender differences in the effects of menthol-
flavored e-cigarettes.
The results of this dissertation suggest that the availability of sweet-flavored e-cigarettes
may be increasing the use of e-cigarettes among youth, while the impact of flavored e-cigarettes
in adult smokers seeking to reduce or quit smoking is less clear. When considering how to
maximize population health, it is important to consider the relative harm of nicotine-delivery
products as well as two key dimensions of e-cigarettes assessed in this dissertation: (1) appeal;
and (2) the ability to suppress smoking reinstatement behavior and nicotine withdrawal
symptoms. Additionally, it is important to consider population-level trends in patterns of use.
Flavored e-cigarettes are most commonly used by nonsmoking youth and young adults, for
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whom there is little demonstrable public health benefit—as evidence indicates that e-cigarettes
are not diverting youth away from combustible cigarettes or being used for harm reduction
purposes (Dutra & Glantz, 2017). An optimal regulatory strategy based on these criteria and
currently available data might entail promoting strict restrictions on the use of e-cigarettes
(particularly flavored varieties) by youth while encouraging smokers to substitute vaping for
smoking. Additional research is needed to determine if flavored e-cigarettes may be more
effective than traditional tobacco flavors at reducing smoking among adults.

Implications
Before the advent of e-cigarettes, federal regulatory strategies intended to reduce the
public health burden of tobacco were relatively straightforward, as they could focus solely on
reducing smoking among youth and adults. In contrast to combustible cigarettes, whose health
effects are known to be uniformly detrimental, e-cigarettes may reduce the adverse health
consequences of combustible tobacco if they are successfully substituted for cigarettes among
chronic smokers. The Tobacco Control Act requires the FDA to regulate tobacco products in a
manner that protects and benefits, “The population as a whole,” considering both the likelihood
that existing tobacco users will stop using such products as well as the likelihood that non-users
will start using tobacco products. In the current tobacco product marketplace, nuanced strategies
that consider cross-product and cross-population differences are needed to optimize the impact of
FDA regulation on the overall health of the population.
The precision regulation paradigm discussed in this dissertation may help achieve this
goal by simultaneously considering the harm flavored e-cigarettes pose to youth and the ways in
which they could benefit adult smokers. An optimal FDA regulatory standard would protect
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youth and young adults from initiating tobacco product use, while maintaining the availability of
non-combustible tobacco products (with substantially fewer health-damaging toxins) for adult
combusted tobacco users who seek to reduce tobacco product-caused disease risk. In sum, the
findings reported in this dissertation concord with and extend previous evidence demonstrating
that flavored e-cigarettes are appealing to youth, while also offering preliminary suggestive
evidence that flavored e-cigarettes may potentially help some adult smokers resist the motivation
to smoke combustible cigarettes during periods of tobacco abstinence.
Although tobacco control measures, including public health interventions (e.g., media
campaigns) and policies (e.g., taxation, age restrictions) have successfully decreased the
prevalence of smoking and reduced tobacco-related death and disease, they have not completely
eliminated the death and disease caused by tobacco products (Arnott, 2013). As the Surgeon
General’s Report stated in 2014, “The current rate of progress in tobacco control is not fast
enough. More needs to be done” (Health & Services, 2014). Since The Act of 2009, the field of
tobacco regulatory science has evolved to include research designed to support the FDA in its
mission to protect public health via regulatory control of tobacco products. This dissertation
utilized the methods of tobacco regulatory science to collect and present data designed to inform
a new framework of precision regulation that may benefit population health.
As stated throughout this dissertation, the FDA’s regulatory purview includes protecting
youth while also promoting and encouraging the development of innovative products and
treatments that: (1) encourage abstinence from tobacco product use; (2) reduce consumption of
tobacco products; and (3) reduce the harm associated with tobacco product use. The
commissioner of the FDA and head of CTP recently stated in an editorial in the New England
Journal of Medicine that the FDA will pursue a regulatory framework that promotes tobacco
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harm reduction, and includes both the reduction of nicotine content in combustible cigarettes and
the use of noncombustible products such as e-cigarettes (Gottlieb & Zeller, 2017). This
framework recognizes that the health risk of tobacco products is primarily derived from the
mechanism of nicotine delivery, and that combustible cigarettes cause the vast majority of
tobacco-related disease (Gottlieb & Zeller, 2017).
This novel and progressive approach creates an opportunity for the use of
noncombustible tobacco products (i.e., e-cigarettes) as harm reduction aids as part of a
comprehensive strategy to reduce the public health burden of tobacco (Yang, 2018). Reducing
the nicotine content of combustible cigarettes below addictive levels and encouraging the use of
alternative nicotine delivery systems (i.e., e-cigarettes) in concert may reduce the prevalence of
smoking (Smith et al., 2018). Yet, there remain a number of key questions that need to be
answered in order to achieve the stated goal of reducing tobacco-related morbidly and mortality
while also simultaneously protecting youth from addiction to new tobacco products. The data
from each of the three studies included in this dissertation begin to answer these questions by
revealing the multifaceted impact of flavored e-cigarettes among youth and adult populations.
It is well established that flavored e-cigarettes are frequently used by youth at e-cigarette
initiation (Ambrose et al., 2015; Corey et al., 2014),

and recent evidence suggests that use of
flavored e-cigarettes may also contribute to persistent e-cigarette use following initiation (Bold et
al., 2016). The finding in Chapter 2 that use of sweet-flavored e-cigarettes was associated with
persistent e-cigarette use over a two-year period is particularly concerning given evidence that:
(1) youth perceive flavored e-cigarettes as less harmful than tobacco-flavored e-cigarettes; (2) e-
cigarettes are associated with the initiation of combustible cigarettes among nonsmoking youth;
and (3) flavored e-cigarettes may contain chemicals that are harmful to respiratory health. Since
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few youth report using e-cigarettes for smoking reduction purposes, the ongoing availability of
flavored e-cigarettes is likely detrimentally impacting the health of youth.
The results of Chapter 3 suggest that use of sweet-flavored e-cigarettes may help smokers
resist the urge to reinstatement smoking following a period of overnight tobacco deprivation
designed to simulate a quit attempt. In comparison to a tobacco-flavored e-cigarette, the
administration of a sweet-flavored e-cigarette delayed the onset of smoking behavior and
resulted in participant’s smoking fewer cigarettes once beginning smoking during the behavioral
smoking task. These results suggest that tobacco may not be the optimal flavoring to facilitate
the substitution of noncombustible products for combustible cigarette smoking. Future research
should compare sweet-flavored e-cigarettes to other flavorings that have demonstrated the ability
to reduce smoking, such as menthol, in order to determine the relative efficacy of sweet-flavored
e-cigarettes.
When interpreting the results of this preliminary study, it is important to consider that this
experiment only assessed the difference between two individual e-cigarette flavors (one sweet-
and one tobacco-flavored) and did not evaluate menthol-flavored e-cigarettes or include smokers
of mentholated cigarettes in the sample. This limitation is important, as previous evidence from
a smoking reduction trial suggests that menthol-flavored e-cigarettes may be particularly
effective at reducing smoking behavior (Litt et al., 2016). Additionally, the smokers of non-
mentholated cigarettes included in this study may differ from menthol smokers in their response
to sweet-flavored e-cigarettes. Future research is needed to compare the effects of a wider
variety of flavored e-cigarettes and other product characteristics on smoking reduction and
cessation in diverse populations of smokers to establish the efficacy of specific e-cigarette
flavorings on reducing motivation to smoke during quit attempts.
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The public health benefit of e-cigarettes will likely be determined by both their efficacy
at reducing smoking and their ability to attract smokers (Abrams, 2014; Kozlowski & Warner,
2017). In addition to reducing smoking reinstatement, this study (and the second laboratory
study included in this dissertation) found that sweet-flavored e-cigarettes were rated as more
appealing than tobacco-flavored e-cigarettes. Hence, if flavorings enhance the ability of e-
cigarettes to reduce motivation to reinstate smoking (i.e., their efficacy) and increase use of e-
cigarettes among smokers (i.e., their reach), they could have a greater positive population-level
impact than currently available cessation treatments (efficacy × reach).
The third dissertation study (Chapter 4) found that the appeal and sensory effects of
flavored e-cigarettes differed by gender, with the results suggesting that menthol-flavored e-
cigarettes may be particularly appealing to female (vs. male) vapers. Thus, the public health
impact of flavored e-cigarettes may depend on the population and context in which they are
being used. As discussed throughout this dissertation, flavored e-cigarettes could simultaneous
harm youth and benefit adult smokers, and this balance could be modulated in by population-
level differences (e.g., gender). The findings from this study have important implications for
tobacco prevention among female youth and gender-specific smoking cessation treatment for
adults, and can be extended to other population-level differences.
Under a precision regulation framework, the risk flavored e-cigarettes pose to youth and
their the potential to aid harm reduction among smokers may not be mutually exclusive. This
question is further complicated by the fact that research scientists and policy experts have
divergent perspectives on whether youth never-smokers or adult chronic smokers are the highest
priority population. Some proponents of e-cigarettes would argue that the net life years and
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quality-adjusted life-years lost to smoking support focusing on adult smokers first, with youth
prevention being a secondary concern.
Recently, the FDA’s CTP commissioned the National Academies of Sciences,
Engineering, and Medicine (NASEM) to assemble a panel of experts to examine the population
health effects of e-cigarette use (National Academies of Sciences, 2018). The report titled,
“Public Health Consequences of e-Cigarettes” systematically reviewed the extant evidence on e-
cigarettes, concluding that while e-cigarettes are not without risk, they may aid smokers in
cessation and reduction of combustible cigarette smoking. Furthermore, the simulation modeling
techniques utilized in the report indicate that there is likely to be a slight net population health
benefit from e-cigarettes in terms of total life-years lost to tobacco until the year 2050. However,
other simulation studies have found that e-cigarette use would harm population health by
increasing the number of chronic cigarette smokers, resulting in an increase in net years of life
lost (Soneji, Sung, Primack, Pierce, & Sargent, 2018).
The simulation approach used in the NASEM report assumes that the health of all
populations are weighted equally, and that the life-years a smoker may gain at the end of their
life by quitting smoking are equivalent to those lost by a nonsmoking adolescent initiating
tobacco use. However, the NASEM report also clearly states that, “Young people who begin
with e-cigarettes are more likely to transition to combustible cigarette use and become smokers
who are at risk to suffer the known health burdens of combustible tobacco cigarettes” (National
Academies of Sciences, 2018). Achieving the proper balance between protecting youth and
aiding adult smokers in cessation efforts requires answering complex regulatory and ethical
questions, and additional evidence regarding the ability of e-cigarettes to successfully aid
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smoking cessation and reduction efforts is needed to more clearly determine the individual and
the population health effects of e-cigarettes.
Elucidating the risks and benefits that flavored e-cigarettes pose to the population as a
whole requires systematic approaches, such as those utilized in the Tobacco Products Scientific
Advisory Committee’s (TPSAC) 2011 report on mentholated combustible cigarettes. The
TPSAC report integrated a wide range of existing data and empirical reviews from hundreds of
preclinical and epidemiological studies as well as population simulation models, ultimately
concluding that, “Removal of menthol cigarettes from the marketplace would benefit public
health in the United States” (Committee, 2011). Determining the public health impact of
flavored e-cigarettes will require utilizing similar strategies, and additional laboratory and
population surveillance research is needed to inform such models. Under a precision regulation
framework, such data can also elucidate whether certain vulnerable subpopulations may be
disproportionately harmed by or benefit from flavored e-cigarettes. It is possible that certain
flavorings exist that are appealing to youth but aversive to adults, which would be logical targets
for restrictions, however, there may also be certain flavorings (e.g., menthol) that are more
appealing to adults than youth. Hence, a one-size-fits-all regulatory approach may not satisfy the
needs of the entire population.
There are several potential solutions to the challenge of flavored e-cigarettes, including
changes in the regulatory classification of e-cigarettes, more rigorous research studies and state
or local action. Sweet-flavored e-cigarettes could be restricted by the FDA in a product standard,
or the FDA could require manufacturers to provide evidence that their product does not produce
perceptions of sweetness as part of the pre-market review process. E-cigarette manufacturers
could submit a modified risk order to the FDA to classify e-cigarettes as Modified Risk Tobacco
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Products (MRTP), as Swedish Match previously did for snus and Philip Morris International is
currently in the process of doing for their IQOS (heat-not-burn) product. This would require
manufacturers to provide data regarding e-cigarettes ability to reduce tobacco-related risks and
improve population health. Similarly, a related option would be to submit an exposure
modification order, which would require providing data to prove that e-cigarettes reduce
exposures to toxins. The FDA could then utilize its regulatory mechanisms to require e-
cigarettes to meet respective product standards and product review requirements, which are
currently delayed until 2022 per the latest extension of the Deeming Rule.
The FDA could also encourage researchers to evaluate the potential of e-cigarettes to
serve as clinical interventions for smoking cessation. Classifying e-cigarettes as investigational
tobacco products (ITP) or investigational new drugs (IND) could inform FDA product standards
and guide product review of e-cigarettes. However, current FDA policies are weighted towards
protecting the public from exposure to potentially toxic substances (e.g., e-cigarettes), and the
FDA requires extensive preclinical testing before conducting controlled trials with e-cigarettes.
As a result, there has been minimal progress in these areas, as the required animal toxicology
studies have prohibited researchers from seeking designations as an ITP.
Despite these difficulties, there has been progress in the field of regulatory science. The
FDA has funded 14 Tobacco Centers of Regulatory Science (TCORS) across the country, with
much research focusing specifically on e-cigarettes. The National Institute on Drug Abuse
(NIDA) is the process of developing a Standardized Research E-Cigarette (SREC) to encourage
research regarding the appeal and withdrawal-suppressive effects of e-cigarettes, however these
research devices are only available in limited flavored varieties.
104
Randomized clinical trials (RCTs) are considered the “gold-standard” for assessing the
efficacy of drugs and therapeutic devices, and are ultimately needed to determine the ability of
flavored e-cigarettes to serve as effective smoking reduction and cessation aids. To date, there
have been no clinical trials in the U.S. assessing the efficacy of e-cigarettes with nicotine as
smoking cessation devices (as e-cigarettes are not approved as drug devices or nicotine
replacement products by the FDA). However, there have been international clinical trials
focused on the use of e-cigarettes (both with and without nicotine) for smoking cessation (Bullen
et al., 2010; Polosa et al., 2011), and several smoking reduction trials in the U.S. involving
nicotine-free e-cigarettes (Przulj et al., 2016; Tseng et al., 2016). Furthermore, results from one
smoking reduction trial in the U.S. that utilized flavored e-cigarette use found that menthol
flavored e-cigarettes (but not sweet-flavored) were more effective than tobacco-flavored e-
cigarettes at reducing smoking (Litt et al., 2016). This finding lends some support to the efficacy
of flavored e-cigarettes as smoking reduction aids, and reinforces the need for research to
differentiate between sweet- and menthol flavorings. There remains a need for RCTs comparing
different e-cigarette devices, with a variety of flavorings and nicotine concentrations, to FDA-
approved pharmacotherapies, particularly in vulnerable, high-risk populations.
Inaction at the federal level has prompted local efforts to stop the sales of flavored
tobacco products. Several municipalities (e.g., New York City, Chicago) have restricted the
sales of combustible flavored tobacco products, however these efforts did not include e-
cigarettes (Farley & Johns, 2016). In June 2017, the city and county of San Francisco prohibited
the sale of all flavored tobacco products, including e-cigarettes (Chen, Green, Chen, Hoke, &
Borzekowski, 2018). These actions could spur the movement to prohibit the sale of flavored
105
tobacco products, much as indoor smoking restrictions and tobacco tax policies originated at
local and state levels (Glantz & Gardiner, 2018).
In contrast to the complete ban on flavored combustible cigarettes, there may be a middle
ground in which certain flavored e-cigarette products that do not disproportionately appeal to
youth and offer a therapeutic benefit to smokers remain available for purchase, while those that
are highly appealing to adolescents are eliminated from the market. One way this could be
achieved is by restricting the availability of flavored e-cigarettes among youth while
simultaneously offering them to adult smokers on the basis of a prescription from a medical
professional, much in the way that nicotine-containing e-cigarettes are currently only legally
available by prescription in Canada (Shiplo, Czoli, & Hammond, 2015). Given suggestive
evidence that menthol-flavored e-cigarettes may help reduce smoking, a regulatory approach
similar to The Act of 2009 (i.e., the elimination of characterizing flavors other than menthol)
could protect youth without adversely affecting adult smokers seeking to use e-cigarettes to quit
smoking.
The FDA has authority to develop product standards that prohibit products with certain
characteristics or constituents (i.e., flavorings) that are determined to have a net negative impact
on the population as a whole. At the time of the Deeming Rule, there was insufficient evidence
to determine if product standards restricting flavorings would benefit the population as a whole.
Recent epidemiological evidence suggests that the prevalence of flavored e-cigarette use differs
by age, with older adults using flavored e-cigarettes at lower rates than young adults and youth
(Bonhomme et al., 2016; Villanti et al., 2017). In the 2014 PATH study, flavored e-cigarette use
was highest among youth (85.3%), followed by young adults (83.4%) and was lowest in adults
over 25 years of age (63.2%) (Villanti et al., 2017). Thus, adult smokers may not be as heavily
106
affected by a reduction in the availability of flavored e-cigarettes whereas restricting flavored
products among youth may have a robust positive effect on the population as a whole. In
concordance with this data, the evidence presented in this dissertation suggests that a new
product standard restricting sweet-flavored e-cigarettes would likely benefit youth and young
adults.
Although restricting the availability of flavored e-cigarettes would likely reduce youth e-
cigarette use, it is unclear if such a standard would adversely impact adult smokers, and more
research is needed in this area. Data from this dissertation can inform the development of
regulatory policies that balance the need to protect youth while also encouraging the innovation
of satisfying and less harmful nicotine-delivery products for adult smokers. This dissertation
also emphasizes the need to consider disparities in tobacco-related health outcomes based on
divergent effects across subpopulations. The application of precision regulatory strategies offers
the potential to prevent new youth from becoming tobacco users while simultaneously
encouraging current users to transition to a lower harm product.

Future Research Directions
The nascent literature on flavored e-cigarette products is relatively sparse compared to
decades of research on combustible cigarettes. The studies included in this dissertation add
novel data to the growing literature on the use and appeal of flavored e-cigarettes, addressing
significant questions facing tobacco control and tobacco regulatory science. Additional data is
needed to extend these findings to more diverse populations and longer periods of observation,
and to identify mechanisms underlying the effects of flavored e-cigarettes on product appeal and
motivation to reinstate smoking. Future research should also examine if use of flavored e-
107
cigarettes leads to increased nicotine dependence and transitions to combustible tobacco products
among youth. Additionally, determining if sweet-flavored e-cigarettes enhance the effectiveness
of e-cigarettes as smoking reduction or cessation aids has important implications for clinical
smoking treatment and the current regulatory debate.
To extend the results detailed in Chapter 2, additional longitudinal data in larger samples
is needed to more fully determine the impact of sweet-flavored e-cigarettes on developmental
patterns of e-cigarette use as well as progression to combustible tobacco product use among
nonsmoking youth. Since this study only examined past 6-month and past 30-day use, research
should also assess prospective associations between use of sweet-flavored e-cigarettes and
frequency of past 30-day vaping and smoking, as it is unknown if use of sweet-flavored e-
cigarettes is prospectively associated with heavier patterns of tobacco product use. Future
research should also examine if use of flavored e-cigarettes is associated with persistent use
beyond the 6-month interval included in this study.
In this study there was not a significant association between sweet-flavored e-cigarette
use and combustible cigarette smoking. It is possible that users of non-sweet-flavored e-
cigarettes (vs. users of sweet-flavored e-cigarettes) may smoke combustible cigarettes because
they have become accustomed to the flavor of tobacco, or alternatively smokers may be drawn to
e-cigarettes with traditional flavorings. Since we did not stratify the sample by smoking status, it
is difficult to parse this association. Future research in larger samples is needed to confirm the
lack of a significant association between sweet-flavored e-cigarette use and combustible cigarette
smoking, and explore possible differences in flavored e-cigarette use by smoking status. Recent
evidence also suggests that use of e-cigarettes with higher nicotine concentrations is
108
prospectively associated with increased vaping and smoking (Goldenson et al., 2017), and
studies should examine the interaction between flavor and nicotine concentration.
The laboratory study included in Chapter 3 compared sweet- and tobacco-flavored e-
cigarettes among smokers of non-mentholated cigarettes, and future research should expand this
assessment to a greater variety of flavorings and a wider range of smokers. Additionally, this
study could be extended by parsing the effects of flavor and nicotine concentration. Since we
did not evaluate the effects of flavor separately from nicotine (i.e., include flavor conditions
without nicotine), research is needed to determine if flavor and nicotine synergistically affect
smoking behavior. Collecting nicotine levels from the blood stream could also elucidate
potential mechanisms through which flavorings may affect smoking reinstatement behavior.
The experimental design of the study in Chapter 4 was intended to assess the acute appeal
and sensory effects of flavored e-cigarettes among young adult vapers, and future studies should
evaluate the more long-term pharmacological effects of nicotine on product appeal. Since this
study only assessed self-reported subjective effects as outcomes and utilized a controlled
administration procedure, future research should also examine the effects of flavored e-cigarettes
on behavioral outcomes and vaping behavior in the natural ecology.
The research described above can provide data on the appeal and dependence potential of
flavored e-cigarettes in order to inform the FDA’s recent Advanced Notices of Proposed
Rulemaking (ANPRM) on flavored tobacco products. The methods used in this dissertation
provide a model for future study of how: (1) product characteristics affect patterns of youth
tobacco product use; (2) the efficacy of novel non-combustible tobacco products (e.g., heat-not-
burn) as smoking reduction and cessation aids; and (3) the impact of flavored tobacco products
109
varies among subpopulations who differ in their levels of vulnerability to tobacco products (e.g.,
racial and ethnic minorities, the mentally ill).

Concluding Remarks
The availability of flavored e-cigarettes is likely contributing to the increasing prevalence
of vaping among youth and may be maintaining persistent use following initiation. However,
preliminary evidence from this dissertation suggests that sweet-flavored e-cigarettes may aid
some adult smokers in resisting smoking reinstatement during periods of tobacco abstinence,
although the mechanisms underlying this association are unclear. The results of this dissertation
also reinforce the need to evaluate the effects of flavored e-cigarettes in diverse populations, as
the appeal and sensory effects of menthol-flavored e-cigarettes were greater in females (vs.
males). Taken together, the three studies in this dissertation can begin to inform a paradigm of
precision regulation that benefits the population as a whole. Innovative research is needed to
systematically address the regulatory challenge of flavored e-cigarettes, informing evidence-
based policies that prioritize the health of youth while simultaneously promoting smoking
cessation and reduction among adult smokers.

110
References

Abrams, D. B. (2014). Promise and peril of e-cigarettes: can disruptive technology make
cigarettes obsolete? JAMA, 311(2), 135-136.
Abrams, D. B., Glasser, A. M., Pearson, J. L., Villanti, A. C., Collins, L. K., & Niaura, R. S.
(2018). Harm Minimization and Tobacco Control: Reframing Societal Views of Nicotine
Use to Rapidly Save Lives. Annual Review of Public Health(0).
Aguirre, C. G., Madrid, J., & Leventhal, A. M. (2015). Tobacco withdrawal symptoms mediate
motivation to reinstate smoking during abstinence. Journal of abnormal psychology,
124(3), 623.
Allem, J. P., Cruz, T. B., Unger, J. B., Toruno, R., Herrera, J., & Kirkpatrick, M. G. (2018).
Return of cartoon to market e-cigarette-related products. Tobacco Control.
doi:10.1136/tobaccocontrol-2018-054437
Allen, J. G., Flanigan, S. S., LeBlanc, M., Vallarino, J., MacNaughton, P., Stewart, J. H., &
Christiani, D. C. (2016). Flavoring chemicals in e-cigarettes: diacetyl, 2, 3-pentanedione,
and acetoin in a sample of 51 products, including fruit-, candy-, and cocktail-flavored e-
cigarettes. Environmental health perspectives, 124(6), 733.
Ambrose, B. K., Day, H. R., Rostron, B., Conway, K. P., Borek, N., Hyland, A., & Villanti, A.
C. (2015). Flavored tobacco product use among us youth aged 12-17 years, 2013-2014.
JAMA, 314(17), 1871-1873.
Anderson, S. J. (2011). Menthol cigarettes and smoking cessation behaviour: a review of tobacco
industry documents. Tobacco control, 20(Suppl 2), ii49-ii56.
Arnott, D. (2013). There's no single endgame. Tobacco control, 22(suppl 1), i38-i39.
Ashley, E. A. (2015). The precision medicine initiative: a new national effort. JAMA, 313(21),
2119-2120.
Ashoor, A., Nordman, J. C., Veltri, D., Yang, K.-H. S., Al Kury, L., Shuba, Y., . . . Shehu, A.
(2013). Menthol binding and inhibition of α7-nicotinic acetylcholine receptors. PloS one,
8(7), e67674.
Audrain-McGovern, J., Strasser, A. A., & Wileyto, E. P. (2016). The impact of flavoring on the
rewarding and reinforcing value of e-cigarettes with nicotine among young adult
smokers. Drug and alcohol dependence.
Babb, S. (2017). Quitting smoking among adults—United States, 2000–2015. MMWR. Morbidity
and mortality weekly report, 65.
Backinger, C. L., Meissner, H. I., & Ashley, D. L. (2016). The FDA “Deeming Rule “and
Tobacco Regulatory Research. Tobacco Regulatory Science, 2(3), 290-293.
Bao, W., Xu, G., Lu, J., Snetselaar, L. G., & Wallace, R. B. (2018). Changes in electronic
cigarette use among adults in the united states, 2014-2016. JAMA, 319(19), 2039-2041.
doi:10.1001/jama.2018.4658
Barbeau, A. M., Burda, J., & Siegel, M. (2013). Perceived efficacy of e-cigarettes versus nicotine
replacement therapy among successful e-cigarette users: a qualitative approach. Addiction
Science & Clinical Practice, 8(1), 5.
Barrett, S. P. (2010). The effects of nicotine, denicotinized tobacco, and nicotine-containing
tobacco on cigarette craving, withdrawal, and self-administration in male and female
smokers. Behavioural Pharmacology, 21(2), 144-152.
doi:10.1097/FBP.0b013e328337be68
111
Barrington-Trimis, J. L., Berhane, K., Unger, J. B., Cruz, T. B., Huh, J., Leventhal, A. M., . . .
Gilreath, T. D. (2015). Psychosocial factors associated with adolescent electronic
cigarette and cigarette use. Pediatrics, 136(2), 308-317.
Barrington-Trimis, J. L., Gibson, L. A., Halpern-Felsher, B., Harrell, M. B., Kong, G., Krishnan-
Sarin, S., . . . Weaver, S. R. (2017). Type of e-cigarette device used among adolescents
and young adults: findings from a pooled analysis of eight studies of 2166 vapers.
Nicotine and Tobacco Research, 20(2), 271-274.
Barrington-Trimis, J. L., Samet, J. M., & McConnell, R. (2014). Flavorings in electronic
cigarettes: an unrecognized respiratory health hazard? JAMA, 312(23), 2493-2494.
Barrington-Trimis, J. L., Urman, R., Berhane, K., Unger, J. B., Cruz, T. B., Pentz, M. A., . . .
McConnell, R. (2016). E-cigarettes and future cigarette use. Pediatrics, 138(1),
e20160379.
Beauchamp, G. K. (2016). Why do we like sweet taste: A bitter tale? Physiology & behavior.
Benowitz, N. (2008). Clinical pharmacology of nicotine: implications for understanding,
preventing, and treating tobacco addiction. Clinical Pharmacology & Therapeutics,
83(4), 531-541.
Benowitz, N. L. (1996). Pharmacology of nicotine: addiction and therapeutics. Annual review of
pharmacology and toxicology, 36(1), 597-613.
Benowitz, N. L. (2009). Pharmacology of nicotine: addiction, smoking-induced disease, and
therapeutics. Annual review of pharmacology and toxicology, 49, 57-71.
Benowitz, N. L., Donny, E. C., & Hatsukami, D. K. (2017). Reduced nicotine content cigarettes,
e cigarettes and the cigarette end game. Addiction, 112(1), 6-7.
Benowitz, N. L., & Goniewicz, M. L. (2013). The regulatory challenge of electronic cigarettes.
JAMA, 310(7), 685-686.
Benowitz, N. L., Herrera, B., & Jacob, P. (2004). Mentholated cigarette smoking inhibits
nicotine metabolism. Journal of Pharmacology and Experimental Therapeutics, 310(3),
1208-1215.
Berg, C. J. (2015). Preferred flavors and reasons for e-cigarette use and discontinued use among
never, current, and former smokers. International Journal of Public Health, 1-12.
Berman, M. L., & Yang, Y. T. (2016). E-Cigarettes, Youth, and the US Food and Drug
Administration’s “Deeming” Regulation. JAMA pediatrics, 170(11), 1039-1040.
Bhatnagar, A. (2016). E-cigarettes and cardiovascular disease risk: evaluation of evidence,
policy implications, and recommendations. Current Cardiovascular Risk Reports, 10(7),
24.
Bold, K. W., Kong, G., Camenga, D. R., Simon, P., Cavallo, D. A., Morean, M. E., & Krishnan-
Sarin, S. (2017). Trajectories of e-cigarette and conventional cigarette use among youth.
Pediatrics, e20171832.
Bold, K. W., Kong, G., Cavallo, D. A., Camenga, D. R., & Krishnan-Sarin, S. (2016). Reasons
for trying e-cigarettes and risk of continued use. Pediatrics, 138(3), e20160895.
Bonhomme, M. G., Holder-Hayes, E., Ambrose, B. K., Tworek, C., Feirman, S. P., King, B. A.,
& Apelberg, B. J. (2016). Flavoured non-cigarette tobacco product use among US adults:
2013–2014. Tobacco control, 25(Suppl 2), ii4-ii13.
Brown, J. E., Luo, W., Isabelle, L. M., & Pankow, J. F. (2014). Candy flavorings in tobacco.
New England Journal of Medicine, 370(23), 2250-2252.
112
Brown, R., Herman, K., Ramsey, S., & Stout, R. (1998). Characteristics of smoking cessation
participants who lapse on quit date. Paper presented at the First International Conference
for the Society for Research on Nicotine and Tobacco.
Brown, R. A., Lejuez, C., Kahler, C. W., & Strong, D. R. (2002). Distress tolerance and duration
of past smoking cessation attempts. Journal of abnormal psychology, 111(1), 180.
Buckell, J., Marti, J., & Sindelar, J. L. (2017). Should Flavors be Banned in E-cigarettes?
Evidence on Adult Smokers and Recent Quitters from a Discrete Choice Experiment.
National Bureau of Economic Research.
Bullen, C., McRobbie, H., Thornley, S., Glover, M., Lin, R., & Laugesen, M. (2010). Effect of
an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal,
user preferences and nicotine delivery: randomised cross-over trial. Tobacco Control,
19(2), 98-103.
Buu, A., Hu, Y. H., Piper, M. E., & Lin, H. C. (2018). The association between e-cigarette use
characteristics and combustible cigarette consumption and dependence symptoms:
Results from a national longitudinal study. Addictive Behaviors, 84, 69-74.
doi:10.1016/j.addbeh.2018.03.035
Camenga, D. R., Morean, M., Kong, G., Krishnan-Sarin, S., Simon, P., & Bold, K. (2018).
Appeal and Use of Customizable E-cigarette Product Features in Adolescents. Tobacco
Regulatory Science, 4(2), 51-60.
Caraballo, R. S., Shafer, P. R., Patel, D., Davis, K. C., & McAfee, T. A. (2017). Quit Methods
Used by US Adult Cigarette Smokers, 2014-2016. Preventing Chronic Disease, 14, E32.
doi:10.5888/pcd14.160600
Carpenter, C. M., Wayne, G. F., & Connolly, G. N. (2005). Designing cigarettes for women: new
findings from the tobacco industry documents. Addiction, 100(6), 837-851.
Carpenter, C. M., Wayne, G. F., & Connolly, G. N. (2007). The role of sensory perception in the
development and targeting of tobacco products. Addiction, 102(1), 136-147.
Carpenter, C. M., Wayne, G. F., Pauly, J. L., Koh, H. K., & Connolly, G. N. (2005). New
cigarette brands with flavors that appeal to youth: tobacco marketing strategies. Health
Affairs, 24(6), 1601-1610.
Carter, L. P., & Griffiths, R. R. (2009). Principles of laboratory assessment of drug abuse
liability and implications for clinical development. Drug and alcohol dependence, 105,
S14-S25.
Carter, L. P., Stitzer, M. L., Henningfield, J. E., O'Connor, R. J., Cummings, K. M., &
Hatsukami, D. K. (2009). Abuse liability assessment of tobacco products including
potential reduced exposure products. Cancer Epidemiology Biomarkers & Prevention,
18(12), 3241-3262.
Carvajal, R., Clissold, D., & Shapiro, J. (2009). Family Smoking Prevention and Tobacco
Control Act: An Overview, The. Food & Drug Law Journal, 64, 717.
Cepeda-Benito, A., Reynoso, J. T., & Erath, S. (2004). Meta-analysis of the efficacy of nicotine
replacement therapy for smoking cessation: differences between men and women.
Journal of consulting and clinical psychology, 72(4), 712.
Chaudhri, N., Caggiula, A. R., Donny, E. C., Palmatier, M. I., Liu, X., & Sved, A. F. (2006).
Complex interactions between nicotine and nonpharmacological stimuli reveal multiple
roles for nicotine in reinforcement. Psychopharmacology, 184(3-4), 353-366.
113
Chen, J. C. (2018). Flavored E-cigarette Use and Cigarette Smoking Reduction and Cessation-A
Large National Study among Young Adult Smokers. Substance Use & Misuse, 1-15.
doi:10.1080/10826084.2018.1455704
Chen, J. C., Das, B., Mead, E. L., & Borzekowski, D. L. (2017). Flavored e-cigarette use and
cigarette smoking susceptibility among youth. Tobacco Regulatory Science, 3(1), 68-80.
Chen, J. C., Green, K. M., Chen, J., Hoke, K. S., & Borzekowski, D. L. (2018). Restricting the
Sale of Flavored E-cigarettes in the US: An Examination of Local Regulations. Tobacco
Regulatory Science, 4(4), 32-40.
Cheney, M. K., Gowin, M., & Wann, T. F. (2016). Electronic Cigarette Use in Straight-to-Work
Young Adults. American journal of health behavior, 40(2), 268-279.
Clapp, P. W., Pawlak, E. A., Lackey, J. T., Keating, J. E., Reeber, S. L., Glish, G. L., & Jaspers,
I. (2017). Flavored E-cigarette Liquids and Cinnamaldehyde Impair Respiratory Innate
Immune Cell Function. American Journal of Physiology-Lung Cellular and Molecular
Physiology, ajplung. 00452.02016.
Cohen, L. M., Collins, F. L., & Britt, D. M. (1997). The effect of chewing gum on tobacco
withdrawal. Addictive behaviors, 22(6), 769-773.
Cohen, L. M., Collins, F. L., VanderVeen, J. W., & Weaver, C. C. (2010). The effect of chewing
gum flavor on the negative affect associated with tobacco abstinence among dependent
cigarette smokers. Addictive behaviors, 35(11), 955-960.
Collins, F. S., & Varmus, H. (2015). A new initiative on precision medicine. New England
Journal of Medicine, 372(9), 793-795.
Committee, T. P. S. A. C. (2011). Menthol cigarettes and public health: review of the scientific
evidence and recommendations. Washington DC: US Food and Drug Administration,
201(1).
Cook, J. W., Piper, M. E., Leventhal, A. M., Schlam, T. R., Fiore, M. C., & Baker, T. B. (2015).
Anhedonia as a component of the tobacco withdrawal syndrome. J Abnormal
Psychology, 124(1), 215-225. doi:10.1037/abn0000016
Cooper, M., Harrell, M. B., Pérez, A., Delk, J., & Perry, C. L. (2016). Flavorings and Perceived
Harm and Addictiveness of E-cigarettes among Youth. Tobacco Regulatory Science,
2(3), 278-289.
Corey, C. G., Ambrose, B. K., Apelberg, B. J., & King, B. A. (2014). Flavored Tobacco Product
Use Among Middle and High School Students—United States, 2014. MMWR. Morbidity
and mortality weekly report, 64(38), 1066-1070.
Brown & Williamson. Youth Cigarette—New Concepts. Marketing Innovations memo to Brown
& Williamson, September 1972, Bates No. 170042014
Cortez-Garland, M., Cohen, L. M., VanderVeen, J. W., & Cook, K. (2010). The effect of
chewing gum on self-reported nicotine withdrawal: Is it the flavor, the act of chewing, or
both? Addictive behaviors, 35(3), 224-228.
Courtemanche, C. J., Palmer, M. K., & Pesko, M. F. (2017). Influence of the flavored cigarette
ban on adolescent tobacco use. American journal of preventive medicine, 52(5), e139-
e146.
Cox, L. S., Tiffany, S. T., & Christen, A. G. (2001). Evaluation of the brief questionnaire of
smoking urges (QSU-brief) in laboratory and clinical settings. Nicotine & Tobacco
Research, 3(1), 7-16.
114
Cubbin, C., Soobader, M. J., & LeClere, F. B. (2010). The intersection of gender and
race/ethnicity in smoking behaviors among menthol and non menthol smokers in the
United States. Addiction, 105(s1), 32-38.
Cummings, K. M., Morley, C., Horan, J., Steger, C., & Leavell, N.-R. (2002). Marketing to
America's youth: evidence from corporate documents. Tobacco control, 11(suppl 1), i5-
i17.
D’Silva, J., Cohn, A. M., Johnson, A. L., & Villanti, A. C. (2017). Differences in Subjective
Experiences to First Use of Menthol and Non-Menthol Cigarettes in a National Sample of
Young Adult Cigarette Smokers. Nicotine & Tobacco Research.
Dai, H., & Hao, J. (2016). Flavored Electronic Cigarette Use and Smoking Among Youth.
Pediatrics, e20162513.
Dawkins, L., & Corcoran, O. (2014). Acute electronic cigarette use: nicotine delivery and
subjective effects in regular users. Psychopharmacology, 231(2), 401-407.
Dawkins, L., Kimber, C., Puwanesarasa, Y., & Soar, K. (2015). First versus second generation electronic cigarettes: predictors of choice and effects on urge to smoke and
withdrawal symptoms. Addiction, 110(4), 669-677.
Dawkins, L., Turner, J., Hasna, S., & Soar, K. (2012). The electronic-cigarette: effects on desire
to smoke, withdrawal symptoms and cognition. Addictive behaviors, 37(8), 970-973.
Dawkins, L., Turner, J., Roberts, A., & Soar, K. (2013). ‘Vaping’profiles and preferences: an
online survey of electronic cigarette users. Addiction, 108(6), 1115-1125.
DeGrandpre, R. J., Bickel, W. K., Higgins, S. T., & Hughes, J. R. (1994). A behavioral economic
analysis of concurrently available money and cigarettes. Journal of the Experimental
Analysis of Behavior, 61(2), 191-201.
DeVito, E. E., Valentine, G. W., Herman, A. I., Jensen, K. P., & Sofuoglu, M. (2016). Effect of
menthol-preferring status on response to intravenous nicotine. Tobacco Regulatory
Science, 2(4), 317-328.
Dutra, L. M., & Glantz, S. A. (2017). E-cigarettes and national adolescent cigarette use: 2004–
2014. Pediatrics, e20162450.
Eaton, D. K., Kann, L., Kinchen, S., Shanklin, S., Ross, J., Hawkins, J., . . . Chyen, D. (2010).
Youth risk behavior surveillance—United States, 2009. MMWR Surveillance Summary,
59(5), 1-142.
Edwards, S. A., Bondy, S. J., Callaghan, R. C., & Mann, R. E. (2014). Prevalence of unassisted
quit attempts in population-based studies: a systematic review of the literature. Addictive
behaviors, 39(3), 512-519.
Eissenberg, T., & Balster, R. L. (2000). Initial tobacco use episodes in children and adolescents:
current knowledge, future directions. Drug and alcohol dependence, 59, 41-60.
England, L. J., Bunnell, R. E., Pechacek, T. F., Tong, V. T., & McAfee, T. A. (2015). Nicotine
and the developing human: a neglected element in the electronic cigarette debate.
American journal of preventive medicine, 49(2), 286-293.
Farley, S. M., & Johns, M. (2016). New York City flavoured tobacco product sales ban
evaluation. Tobacco control, tobaccocontrol-2015-052418.
Farsalinos, K. E., Romagna, G., Tsiapras, D., Kyrzopoulos, S., Spyrou, A., & Voudris, V.
(2013). Impact of flavour variability on electronic cigarette use experience: an internet
survey. International journal of environmental research and public health, 10(12), 7272-
7282.
115
Farsalinos, K. E., Romagna, G., Tsiapras, D., Kyrzopoulos, S., & Voudris, V. (2014).
Characteristics, perceived side effects and benefits of electronic cigarette use: a
worldwide survey of more than 19,000 consumers. International journal of
environmental research and public health, 11(4), 4356-4373.
Faulkner, P., Petersen, N., Ghahremani, D. G., Cox, C. M., Tyndale, R. F., Hellemann, G. S., &
London, E. D. (2018). Sex differences in tobacco withdrawal and responses to smoking
reduced-nicotine cigarettes in young smokers. Psychopharmacology (Berl), 235(1), 193-
202. doi:10.1007/s00213-017-4755-x
Feirman, S. P., Lock, D., Cohen, J. E., Holtgrave, D. R., & Li, T. (2015). Flavored Tobacco
Products in the United States: A Systematic Review Assessing Use and Attitudes.
Nicotine & Tobacco Research, ntv176.
Foltin, R. W., Ward, A. S., Collins, E. D., Haney, M., Hart, C. L., & Fischman, M. W. (2003).
The effects of venlafaxine on the subjective, reinforcing, and cardiovascular effects of
cocaine in opioid-dependent and non-opioid-dependent humans. Experimental and
clinical psychopharmacology, 11(2), 123.
Food, & Drug Administration, H. (2010). Regulations restricting the sale and distribution of
cigarettes and smokeless tobacco to protect children and adolescents. Final rule. Federal
Register, 75(53), 13225.
Food, & Drug Administration, H. (2016). Deeming Tobacco Products To Be Subject to the
Federal Food, Drug, and Cosmetic Act, as Amended by the Family Smoking Prevention
and Tobacco Control Act; Restrictions on the Sale and Distribution of Tobacco Products
and Required Warning Statements for Tobacco Products. Final rule. Federal Register,
81(90), 28973.
Foulds, J., Veldheer, S., Yingst, J., Hrabovsky, S., Wilson, S. J., Nichols, T. T., & Eissenberg, T.
(2015). Development of a questionnaire for assessing dependence on electronic cigarettes
among a large sample of ex-smoking E-cigarette users. Nicotine & Tobacco Research,
17(2), 186-192.
Franken, I. H., Rassin, E., & Muris, P. (2007). The assessment of anhedonia in clinical and non-
clinical populations: further validation of the Snaith–Hamilton Pleasure Scale (SHAPS).
Journal of affective disorders, 99(1), 83-89.
Glantz, S. A., & Gardiner, P. (2018). Local Movement to Ban Menthol Tobacco Products as a
Result of Federal Inaction. JAMA Internal Medicine.
doi:10.1001/jamainternmed.2018.0053
Goldenson, N. I., Kirkpatrick, M. G., Barrington-Trimis, J. L., Pang, R. D., McBeth, J. F., Pentz,
M. A., . . . Leventhal, A. M. (2016). Effects of Sweet Flavorings and Nicotine on the
Appeal and Sensory Properties of e-Cigarettes Among Young Adult Vapers: Application
of a Novel Methodology. Drug and alcohol dependence.
Goldenson, N. I., Leventhal, A. M., Stone, M. D., McConnell, R. S., & Barrington-Trimis, J. L.
(2017). Associations of Electronic Cigarette Nicotine Concentration With Subsequent
Cigarette Smoking and Vaping Levels in Adolescents. JAMA pediatrics. 171(12), 1192-
1199
Goletiani, N. V., Siegel, A. J., Lukas, S. E., & Hudson, J. I. (2015). The effects of smoked
nicotine on measures of subjective States and hypothalamic-pituitary-adrenal axis
hormones in women during the follicular and luteal phases of the menstrual cycle.
Journal of Addiction Medicine, 9(3), 195.
116
Goniewicz, M. L., Gawron, M., Smith, D. M., Peng, M., Jacob, P., & Benowitz, N. L. (2017).
Exposure to nicotine and selected toxicants in cigarette smokers who switched to
electronic cigarettes: a longitudinal within-subjects observational study. Nicotine &
Tobacco Research, 19(2), 160-167.
Goniewicz, M. L., Knysak, J., Gawron, M., Kosmider, L., Sobczak, A., Kurek, J., . . . Havel, C.
(2014). Levels of selected carcinogens and toxicants in vapour from electronic cigarettes.
Tobacco control, 23(2), 133-139.
Gottlieb, S., & Zeller, M. (2017). A nicotine-focused framework for public health. New England
Journal of Medicine, 377(12), 1111-1114.
Gritz, E. R., Nielsen, I. R., & Brooks, L. A. (1996). Smoking cessation and gender: the influence
of physiological, psychological, and behavioral factors. Journal of the American Medical
Women's Association (1972), 51(1-2), 35-42.
Guillot, C. R., Zvolensky, M. J., & Leventhal, A. M. (2015). Differential associations between
components of anxiety sensitivity and smoking-related characteristics. Addictive
behaviors, 40, 39-44.
Hajek, P. (2014). Electronic cigarettes have a potential for huge public health benefit. BMC
medicine, 12(1), 225.
Hajek, P., Etter, J. F., Benowitz, N., Eissenberg, T., & McRobbie, H. (2014). Electronic
cigarettes: review of use, content, safety, effects on smokers and potential for harm and
benefit. Addiction, 109(11), 1801-1810.
Hajek, P., Przulj, D., Phillips, A., Anderson, R., & McRobbie, H. (2017). Nicotine delivery to
users from cigarettes and from different types of e-cigarettes. Psychopharmacology,
234(5), 773.
Haney, M., Collins, E. D., Ward, A. S., Foltin, R. W., & Fischman, M. W. (1999). Effect of a
selective dopamine D1 agonist (ABT-431) on smoked cocaine self-administration in
humans. Psychopharmacology, 143(1), 102-110.
Hans, M., Wilhelm, M., & Swandulla, D. (2012). Menthol suppresses nicotinic acetylcholine
receptor functioning in sensory neurons via allosteric modulation. Chemical senses,
37(5), 463-469.
Harrell, M., Weaver, S., Loukas, A., Creamer, M., Marti, C., Jackson, C., . . . Pechacek, T.
(2016). Flavored e-cigarette use: Characterizing youth, young adult, and adult users.
Preventive Medicine Reports. 5, 33-40
Harrell, M. B., Loukas, A., Jackson, C. D., Marti, C. N., & Perry, C. L. (2017). Flavored
Tobacco Product Use among Youth and Young Adults: What if Flavors Didn't Exist?
Tobacco Regulatory Science, 3(2), 168-173.
Hart, C. L., Ward, A. S., Collins, E. D., Haney, M., & Foltin, R. W. (2004). Gabapentin
maintenance decreases smoked cocaine-related subjective effects, but not self-
administration by humans. Drug and alcohol dependence, 73(3), 279-287.
Hartmann Boyce, J., McRobbie, H., Bullen, C., Begh, R., Stead, L. F., & Hajek, P. (2016).
Electronic cigarettes for smoking cessation. The Cochrane Library.
Health, U. D. o., & Services, H. (2014). The health consequences of smoking—50 years of
progress: a report of the Surgeon General. Atlanta, GA: US Department of Health and
Human Services, Centers for Disease Control and Prevention, National Center for
Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 17.
US Department of Health and Human Services (2016). E-Cigarette use among youth and young
adults. A report of the Surgeon General. Atlanta, GA: US Department of Health and
117
Human Services, Centers for Disease Control and Prevention, National Center for
Chronic Disease Prevention and Health Promotion, Office on Smoking and Health.
Heatherton, T. F., Kozlowski, L. T., Frecker, R. C., & Fagerstrom, K. O. (1991). The Fagerström
test for nicotine dependence: a revision of the Fagerstrom Tolerance Questionnaire.
British journal of addiction, 86(9), 1119-1127.
Heishman, S. J., Singleton, E. G., & Pickworth, W. B. (2008). Reliability and validity of a Short
Form of the Tobacco Craving Questionnaire. Nicotine & Tobacco Research, 10(4), 643-
651.
Helen, G. S., Dempsey, D. A., Havel, C. M., Jacob, P., & Benowitz, N. L. (2017). Impact of e-
liquid flavors on nicotine intake and pharmacology of e-cigarettes. Drug and alcohol
dependence.
Helen, G. S., Ross, K. C., Dempsey, D. A., Havel, C. M., Jacob, P., & Benowitz, N. L. (2016).
Nicotine Delivery and Vaping Behavior during ad libitum E-cigarette Access. Tobacco
Regulatory Science, 2(4), 363-376.
Helen, G. S., Shahid, M., Chu, S., & Benowitz, N. L. (2018). Impact of e-liquid flavors on e-
cigarette vaping behavior. Drug Alcohol Depend, 189, 42-48.
doi:10.1016/j.drugalcdep.2018.04.032
Henningfield, J. E. (2011). Tobacco psychopharmacology and public health policy: it takes a
community. Experimental and Clinical Psychopharmacology, 19(4), 249-262.
doi:10.1037/a0024316
Henningfield, J. E., Hatsukami, D. K., Zeller, M., & Peters, E. (2011). Conference on abuse
liability and appeal of tobacco products: Conclusions and recommendations. Drug and
alcohol dependence, 116(1), 1-7.
Hoffman, A. C., Salgado, R. V., Dresler, C., Faller, R. W., & Bartlett, C. (2016). Flavour
preferences in youth versus adults: a review. Tobacco control, tobaccocontrol-2016-
053192.
Hong, H., Barrington-Trimis, J., Liu, F., Urman, R., & McConnell, R. (2017). Reasons For
Electronic Cigarette Use Among Southern California Young Adults. In A16. WHY
SHOULD WE BE CONCERNED ABOUT E-CIGARETTES? (pp. A1022-A1022):
American Thoracic Society.
Hughes, J. R. (1992). Tobacco withdrawal in self-quitters. Journal of consulting and clinical
psychology, 60(5), 689.
Hughes, J. R. (1994). Nicotine withdrawal, dependence, and abuse. DSM-IV Sourcebook, 1, 109-
116.
Hughes, J. R. (2007). Effects of abstinence from tobacco: etiology, animal models,
epidemiology, and significance: a subjective review. Nicotine & Tobacco Research, 9(3),
329-339.
Hughes, J. R., & Hatsukami, D. (1986). Signs and symptoms of tobacco withdrawal. Archives of
general psychiatry, 43(3), 289-294.
Husten, C. G., & Deyton, L. R. (2013). Understanding the Tobacco Control Act: efforts by the
US Food and Drug Administration to make tobacco-related morbidity and mortality part
of the USA's past, not its future. The Lancet, 381(9877), 1570-1580.
Jackler, R. K., & Ramamurthi, D. (2016). Unicorns cartoons: marketing sweet and creamy e-
juice to youth. Tobacco control, tobaccocontrol-2016-053206.
Johnston, L. D., Miech, R. A., O'Malley, P. M., Bachman, J. G., Schulenberg, J. E., & Patrick,
M. E. (2017). Monitoring the future national survey results on drug use: 1975–2016:
118
overview of key findings on adolescent drug Use. Ann Arbor: Institute for Social
Research, The University of Michigan; 2017.
Kalkhoran, S., Alvarado, N., Vijayaraghavan, M., Lum, P. J., Yuan, P., & Satterfield, J. M.
(2017). Patterns of and reasons for electronic cigarette use in primary care patients.
Journal of General Internal Medicine, 32(10), 1122-1129. doi:10.1007/s11606-017-
4123-x
Kalkhoran, S., & Glantz, S. A. (2016). E-cigarettes and smoking cessation in real-world and
clinical settings: a systematic review and meta-analysis. The Lancet Respiratory
Medicine, 4(2), 116-128.
Kampov-Polevoy, A. B., Alterman, A., Khalitov, E., & Garbutt, J. C. (2006). Sweet preference
predicts mood altering effect of and impaired control over eating sweet foods. Eating
behaviors, 7(3), 181-187.
Kaur, G., Muthumalage, T., & Rahman, I. (2018). Mechanisms of toxicity and biomarkers of
flavoring and flavor enhancing chemicals in emerging tobacco and non-tobacco products.
Toxicology Letters, 288, 143-155. doi:10.1016/j.toxlet.2018.02.025
Khoudigian, S., Devji, T., Lytvyn, L., Campbell, K., Hopkins, R., & O’Reilly, D. (2016). The
efficacy and short-term effects of electronic cigarettes as a method for smoking cessation:
a systematic review and a meta-analysis. International journal of public health, 61(2),
257-267.
Kim, H., Davis, A. H., Dohack, J. L., & Clark, P. I. (2016a). E-Cigarettes Use Behavior and
Experience of Adults: Qualitative Research Findings to Inform E-Cigarette Use Measure
Development. Nicotine & Tobacco Research, ntw175.
Kim, H., Lim, J., Buehler, S. S., Brinkman, M. C., Johnson, N. M., Wilson, L., . . . Clark, P. I.
(2016b). Role of sweet and other flavours in liking and disliking of electronic cigarettes.
Tobacco control, tobaccocontrol-2016-053221.
King, B. A., Tynan, M. A., Dube, S. R., & Arrazola, R. (2014). Flavored-little-cigar and
flavored-cigarette use among US middle and high school students. Journal of adolescent
health, 54(1), 40-46.
Kirkpatrick, M. G., Cruz, T. B., Goldenson, N. I., Allem, J.-P., Chu, K.-H., Pentz, M. A., &
Unger, J. B. (2017). Electronic cigarette retailers use Pokémon Go to market products.
Tobacco control, tobaccocontrol-2016-053369.
Kistler, C. E., Crutchfield, T. M., Sutfin, E. L., Ranney, L. M., Berman, M. L., Zarkin, G. A., &
Goldstein, A. O. (2017). Consumers’ Preferences for Electronic Nicotine Delivery
System Product Features: A Structured Content Analysis. International journal of
environmental research and public health, 14(6), 613.
Klager, S., Vallarino, J., MacNaughton, P., Christiani, D. C., Lu, Q., & Allen, J. G. (2017).
Flavoring Chemicals and Aldehydes in E-Cigarette Emissions. Environmental Science &
Technology, 51(18), 10806-10813.
Kong, G., & Krishnan-Sarin, S. (2017). A call to end the epidemic of adolescent E-cigarette use.
Drug & Alcohol Dependence, 174, 215-221.
Kong, G., Morean, M. E., Cavallo, D. A., Camenga, D. R., & Krishnan-Sarin, S. (2014). Reasons
for electronic cigarette experimentation and discontinuation among adolescents and
young adults. Nicotine & Tobacco Research, ntu257.
Kosmider, L., Sobczak, A., Prokopowicz, A., Kurek, J., Zaciera, M., Knysak, J., . . . Goniewicz,
M. L. (2016). Cherry-flavoured electronic cigarettes expose users to the inhalation
irritant, benzaldehyde. Thorax, thoraxjnl-2015-207895.
119
Kostygina, G., Glantz, S. A., & Ling, P. M. (2014). Tobacco industry use of flavours to recruit
new users of little cigars and cigarillos. Tobacco control, tobaccocontrol-2014-051830.
Kozlowski, L. T., & Warner, K. E. (2017). Adolescents and e-cigarettes: Objects of concern may
appear larger than they are. Drug & Alcohol Dependence, 174, 209-214.
Kralikova, E., Novak, J., West, O., Kmetova, A., & Hajek, P. (2013). Do e-cigarettes have the
potential to compete with conventional cigarettes?: a survey of conventional cigarette
smokers’ experiences with e-cigarettes. CHEST Journal, 144(5), 1609-1614.
Krishnan-Sarin, S., Green, B. G., Kong, G., Cavallo, D. A., Jatlow, P., Gueorguieva, R., . . .
O’Malley, S. S. (2017). Studying the interactive effects of menthol and nicotine among
youth: An examination using e-cigarettes. Drug & Alcohol Dependence.
Krishnan-Sarin, S., Morean, M., Camenga, D., Cavallo, D. A., & Kong, G. (2014). E-cigarette
use among high school and middle school adolescents in Connecticut. Nicotine &
Tobacco Research, ntu243.
Krull, J. L., & MacKinnon, D. P. (2001). Multilevel modeling of individual and group level
mediated effects. Multivariate behavioral research, 36(2), 249-277.
Krüsemann, E. J. Z., Boesveldt, S., de Graaf, K., & Talhout, R. (2018). An E-liquid Flavor
Wheel: A Shared Vocabulary based on Systematically Reviewing E-liquid Flavor
Classifications in Literature. Nicotine & Tobacco Research.
Lenoir, M., Serre, F., Cantin, L., & Ahmed, S. H. (2007). Intense sweetness surpasses cocaine
reward. PloS one, 2(8), e698.
Leventhal, A. M., Stone, M. D., Andrabi, N., Barrington-Trimis, J., Strong, D. R., Sussman, S.,
& Audrain-McGovern, J. (2016). Association of e-Cigarette Vaping and Progression to
Heavier Patterns of Cigarette Smoking. JAMA, 316(18), 1918-1920.
Leventhal, A. M., Strong, D. R., Kirkpatrick, M. G., Unger, J. B., Sussman, S., Riggs, N. R., . . .
Audrain-McGovern, J. (2015). Association of Electronic Cigarette Use With Initiation of
Combustible Tobacco Product Smoking in Early Adolescence. JAMA, 314(7), 700-707.
doi:10.1001/jama.2015.8950
Leventhal, A. M., Strong, D. R., Sussman, S., Kirkpatrick, M. G., Unger, J. B., Barrington-
Trimis, J. L., & Audrain-McGovern, J. (2016). Psychiatric comorbidity in adolescent
electronic and conventional cigarette use. Journal of Psychiatric Research, 73, 71-78.
doi:10.1016/j.jpsychires.2015.11.008
Lewis, M. J., & Wackowski, O. (2006). Dealing with an innovative industry: a look at flavored
cigarettes promoted by mainstream brands. American Journal of Public Health, 96(2),
244-251.
Litt, M. D., Duffy, V., & Oncken, C. (2016). Cigarette smoking and electronic cigarette vaping
patterns as a function of e-cigarette flavourings. Tobacco control, tobaccocontrol-2016-
053223.
McConnell, R., Barrington-Trimis, J. L., Wang, K., Urman, R., Hong, H., Unger, J., . . . Berhane,
K. (2017). Electronic cigarette use and respiratory symptoms in adolescents. American
journal of respiratory and critical care medicine, 195(8), 1043-1049.
McCulloch, C. E., & Neuhaus, J. M. (2001). Generalized linear mixed models: Wiley Online
Library.
McKee, S. A. (2009). Developing human laboratory models of smoking lapse behavior for
medication screening. Addiction biology, 14(1), 99-107.
120
McMillen, R. C., Gottlieb, M. A., Shaefer, R. M. W., Winickoff, J. P., & Klein, J. D. (2015).
Trends in electronic cigarette use among US adults: use is increasing in both smokers and
nonsmokers. Nicotine & Tobacco Research, 17(10), 1195-1202.
McNair, D. M. (1971). Manual profile of mood states. Educational & Industrial testing service.
McNeil, A., Brose, L., Calder, R., Hitchman, S., Hajek, P., & McRobbie, H. (2016). E-
cigarettes: an evidence update. A report commissioned by Public Health England. In:
Available online a t: www. gov. uk/government/publications/e-cigarettes-an-evidence-
updat e (2015, Last accessed 13th November 2015).
Miao, S., Beach, E. S., Sommer, T. J., Zimmerman, J. B., & Jordt, S.-E. (2016). High-Intensity
Sweeteners in Alternative Tobacco Products. Nicotine & Tobacco Research, ntw141.
Miech, R., Patrick, M. E., O'Malley, P. M., & Johnston, L. D. (2016). What are kids vaping?
Results from a national survey of US adolescents. Tobacco control.
doi:10.1136/tobaccocontrol-2016-053014
Moheimani, R. S., Bhetraratana, M., Yin, F., Peters, K. M., Gornbein, J., Araujo, J. A., &
Middlekauff, H. R. (2017). Increased cardiac sympathetic activity and oxidative stress in
habitual electronic cigarette users: implications for cardiovascular risk. JAMA cardiology,
2(3), 278-284.
Moore, D., Aveyard, P., Connock, M., Wang, D., Fry-Smith, A., & Barton, P. (2009).
Effectiveness and safety of nicotine replacement therapy assisted reduction to stop
smoking: systematic review and meta-analysis. BMJ, 338, b1024.
Morean, M., Butler, E., Bold, K., Kong, G., Camenga, D., Cavallo, D., . . . Krishnan-Sarin, S.
(2018). Preferring more e-cigarette flavors is associated with e-cigarette use frequency
among adolescents but not adults. PloS one, 13(1), e0189015-e0189015.
Murthy, V. H. (2017). E-Cigarette Use Among Youth and Young Adults: A Major Public Health
Concern. JAMA pediatrics, 171(3), 209-210.
National Academies of Sciences, E., and Medicine. (2018). Public health consequences of e-
cigarettes. National Academies Press.
Nutt, D. J., Phillips, L. D., Balfour, D., Curran, H. V., Dockrell, M., Foulds, J., . . . Polosa, R.
(2014). Estimating the harms of nicotine-containing products using the MCDA approach.
European addiction research, 20(5), 218-225.
Nutt, D. J., Phillips, L. D., Balfour, D., Curran, H. V., Dockrell, M., Foulds, J., . . . Ramsey, J.
(2016). E-cigarettes are less harmful than smoking. The Lancet, 387(10024), 1160-1162.
Oncken, C., Feinn, R., Covault, J., Duffy, V., Dornelas, E., Kranzler, H. R., & Sankey, H. Z.
(2015a). Genetic vulnerability to menthol cigarette preference in women. Nicotine &
Tobacco Research, 17(12), 1416-1420.
Oncken, C. A., Litt, M. D., McLaughlin, L. D., & Burki, N. A. (2015b). Nicotine concentrations
with electronic cigarette use: effects of sex and flavor. Nicotine & Tobacco Research,
17(4), 473-478. doi:10.1093/ntr/ntu232
Oncken, C. A., Litt, M. D., McLaughlin, L. D., & Burki, N. A. (2015c). Nicotine concentrations
with electronic cigarette use: effects of sex and flavor. Nicotine & Tobacco Research,
17(4), 473-478.
Paolini, M., & De Biasi, M. (2011). Mechanistic insights into nicotine withdrawal. Biochemical
pharmacology, 82(8), 996-1007.
Patrick, M. E., Miech, R. A., Carlier, C., O'Malley, P. M., Johnston, L. D., & Schulenberg, J. E.
(2016). Self-reported reasons for vaping among 8th, 10th, and 12th graders in the US:
Nationally-representative results. Drug and alcohol dependence.
121
Pepper, J., Ribisl, K., & Brewer, N. (2016). Adolescents' interest in trying flavoured e-cigarettes.
Tobacco control, tobaccocontrol-2016-053174.
Perkins, K. A. (1999). Nicotine discrimination in men and women. Pharmacology Biochemistry
and Behavior, 64(2), 295-299.
Perkins, K. A. (2001). Smoking cessation in women. CNS drugs, 15(5), 391-411.
Perkins, K. A., Gerlach, D., Vender, J., Grobe, J., Meeker, J., & Hutchison, S. (2001). Sex
differences in the subjective and reinforcing effects of visual and olfactory cigarette
smoke stimuli. Nicotine & Tobacco Research, 3(2), 141-150.
doi:10.1080/14622200110043059
Perkins, K. A., Jacobs, L., Sanders, M., & Caggiula, A. R. (2002). Sex differences in the
subjective and reinforcing effects of cigarette nicotine dose. Psychopharmacology (Berl),
163(2), 194-201. doi:10.1007/s00213-002-1168-1
Perkins, K. A., & Karelitz, J. L. (2015). Sex differences in acute relief of abstinence-induced
withdrawal and negative affect due to nicotine content in cigarettes. Nicotine Tob Res,
17(4), 443-448. doi:10.1093/ntr/ntu150
Perkins, K. A., Kunkle, N., & Karelitz, J. L. (2017). Threshold dose for behavioral
discrimination of cigarette nicotine content in menthol vs. non-menthol smokers.
Psychopharmacology, 234(8), 1255-1265.
Perkins, K. A., & Scott, J. (2008). Sex differences in long-term smoking cessation rates due to
nicotine patch. Nicotine & Tobacco Research, 10(7), 1245-1251.
Physicians, T. A. G. o. t. R. C. o. (2016). Nicotine without smoke—tobacco harm reduction.
Paper presented at the Royal College of Physicians.
Piasecki, T. M. (2006). Relapse to smoking. Clinical Psychology Review, 26(2), 196-215.
Piñeiro, B., Correa, J. B., Simmons, V. N., Harrell, P. T., Menzie, N. S., Unrod, M., . . . Brandon,
T. H. (2016). Gender differences in use and expectancies of e-cigarettes: Online survey
results. Addictive behaviors, 52, 91-97.
Polosa, R., Caponnetto, P., Morjaria, J. B., Papale, G., Campagna, D., & Russo, C. (2011). Effect
of an electronic nicotine delivery device (e-Cigarette) on smoking reduction and
cessation: a prospective 6-month pilot study. BMC public health, 11(1), 786.
Polosa, R., Cibella, F., Caponnetto, P., Maglia, M., Prosperini, U., Russo, C., & Tashkin, D.
(2017a). Health impact of E-cigarettes: a prospective 3.5-year study of regular daily users
who have never smoked. Scientific reports, 7(1), 13825.
Polosa, R., Rodu, B., Caponnetto, P., Maglia, M., & Raciti, C. (2013). A fresh look at tobacco
harm reduction: the case for the electronic cigarette. Harm reduction journal, 10(1), 1.
Polosa, R., Russell, C., Nitzkin, J., & Farsalinos, K. E. (2017). A critique of the US Surgeon
General’s conclusions regarding e-cigarette use among youth and young adults in the
United States of America. Harm reduction journal, 14(1), 61.
Prescott, E., Hippe, M., Schnohr, P., Hein, H. O., & Vestbo, J. (1998). Smoking and risk of
myocardial infarction in women and men: longitudinal population study. BMJ,
316(7137), 1043.
Primack, B. A., Soneji, S., Stoolmiller, M., Fine, M. J., & Sargent, J. D. (2015). Progression to
traditional cigarette smoking after electronic cigarette use among US adolescents and
young adults. JAMA pediatrics, 169(11), 1018-1023.
Przulj, D., McRobbie, H., & Hajek, P. (2016). Effects of Nicotine-Free E-Cigarettes on Urges to
Smoke and Cigarette Withdrawal Symptoms: A Randomised Cross-Over Study. Journal
of Addiction Research and Therapy, 7(259), 2.
122
Ramôa, C. P., Hiler, M. M., Spindle, T. R., Lopez, A. A., Karaoghlanian, N., Lipato, T., . . .
Eissenberg, T. (2015). Electronic cigarette nicotine delivery can exceed that of
combustible cigarettes: a preliminary report. Tobacco control, tobaccocontrol-2015-
052447.
Rath, J. M., Villanti, A. C., Williams, V. F., Richardson, A., Pearson, J. L., & Vallone, D. M.
(2016). Correlates of current menthol cigarette and flavored other tobacco product use
among US young adults. Addictive behaviors.
Richardson, A., Pearson, J., Xiao, H., Stalgaitis, C., & Vallone, D. (2014). Prevalence, harm
perceptions, and reasons for using noncombustible tobacco products among current and
former smokers. American Journal of Public Health, 104(8), 1437-1444.
Ritter, A., Ritter, A., Cameron, J., Ritter, A., & Cameron, J. (2006). A review of the efficacy and
effectiveness of harm reduction strategies for alcohol, tobacco and illicit drugs. Drug and
alcohol review, 25(6), 611-624.
Romagna, G., Allifranchini, E., Bocchietto, E., Todeschi, S., Esposito, M., & Farsalinos, K. E.
(2013). Cytotoxicity evaluation of electronic cigarette vapor extract on cultured
mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette smoke
extract. Inhalation toxicology, 25(6), 354-361.
Rosbrook, K., & Green, B. G. (2016). Sensory effects of menthol and nicotine in an E-cigarette.
Nicotine & Tobacco Research, ntw019.
Rose, J. E. (2006). Nicotine and nonnicotine factors in cigarette addiction. Psychopharmacology,
184(3-4), 274-285.
Rose, J. E., Salley, A., Behm, F. M., Bates, J. E., & Westman, E. C. (2010). Reinforcing effects
of nicotine and non-nicotine components of cigarette smoke. Psychopharmacology,
210(1), 1-12.
Rubin, D. B. (2004). Multiple imputation for nonresponse in surveys (Vol. 81): John Wiley &
Sons.
Rubinstein, M. L., Delucchi, K., Benowitz, N. L., & Ramo, D. E. (2018). Adolescent Exposure
to Toxic Volatile Organic Chemicals From E-Cigarettes. Pediatrics.
doi:10.1542/peds.2017-3557
Russell, C., Dickson, T., & McKeganey, N. (2017). Advice from Former-Smoking E-Cigarette
Users to Current Smokers on How to Use E-Cigarettes as Part of an Attempt to Quit
Smoking. Nicotine & Tobacco Research.
Russell, C., McKeganey, N., Dickson, T., & Nides, M. (2018). Changing patterns of first e-
cigarette flavor used and current flavors used by 20,836 adult frequent e-cigarette users in
the USA. Harm Reduction Journal, 15(1), 33. doi:10.1186/s12954-018-0238-6
Russell, M. (1976). Low-tar medium-nicotine cigarettes: a new approach to safer smoking. BMJ,
1(6023), 1430-1433.
Rutten, L. J. F., Blake, K. D., Agunwamba, A. A., Grana, R. A., Wilson, P. M., Ebbert, J. O., . . .
Leischow, S. J. (2015). Use of e-cigarettes among current smokers: associations among
reasons for use, quit intentions, and current tobacco use. Nicotine & Tobacco Research,
17(10), 1228-1234.
Samet, J. M., Pentz, M. A., & Unger, J. B. (2016). Flavoured tobacco products and the public's
health: lessons from the TPSAC menthol report. Tobacco control, tobaccocontrol-2016-
053208.
Saunders, J. B., Aasland, O. G., & Organization, W. H. (1987). WHO Collaborative Project on
the Identification and Treatment of Persons with Harmful Alcohol Consumption: Report
123
on Phase 1, the Development of a Screening Instrument: World Health Organization
Geneva.
Schoenborn, C. A., & Gindi, R. M. (2015). Electronic Cigarette Use Among Adults: United
States, 2014. NCHS data brief(217), 1-8.
Schweitzer, R. J., Wills, T. A., & Behner, J. D. (2017). E-cigarette Use and Indicators of
Cardiovascular Disease Risk. Current Epidemiology Reports, 4(3), 248-257.
Shahab, L., Goniewicz, M. L., Blount, B. C., Brown, J., McNeill, A., Alwis, K. U., . . . West, R.
(2017). Nicotine, Carcinogen, and Toxin Exposure in Long-Term E-Cigarette and
Nicotine Replacement Therapy UsersA Cross-sectional StudyE-Cigarettes and Toxin
Exposure. Annals of internal medicine, 166(6), 390-400.
Shang, C., Huang, J., Chaloupka, F. J., & Emery, S. L. (2017). The impact of flavour, device
type and warning messages on youth preferences for electronic nicotine delivery systems:
evidence from an online discrete choice experiment. Tobacco control, tobaccocontrol-
2017-053754.
Shiffman, S., Patten, C., Gwaltney, C., Paty, J., Gnys, M., Kassel, J., . . . Balabanis, M. (2006).
Natural history of nicotine withdrawal. Addiction, 101(12), 1822-1832.
Shiplo, S., Czoli, C. D., & Hammond, D. (2015). E-cigarette use in Canada: prevalence and
patterns of use in a regulated market. BMJ open, 5(8), e007971.
Sidney, S., Tekawa, I., & Friedman, G. D. (1989). Mentholated cigarette use among multiphasic
examinees, 1979-86. American Journal of Public Health, 79(10), 1415-1416.
Singh, T. (2016). Tobacco use among middle and high school students—United States, 2011–
2015. MMWR. Morbidity and mortality weekly report, 65.
Skinner, H. A. (1982). The drug abuse screening test. Addictive behaviors, 7(4), 363-371.
Smith, S. S., Piper, M. E., Bolt, D. M., Fiore, M. C., Wetter, D. W., Cinciripini, P. M., & Baker,
T. B. (2010). Development of the brief Wisconsin inventory of smoking dependence
motives. Nicotine & Tobacco Research, 12(5), 489-499.
Smith, T. T., Hatsukami, D. K., Benowitz, N. L., Colby, S. M., McClernon, F. J., Strasser, A. A.,
. . . Donny, E. C. (2018). Whether to push or pull? Nicotine reduction and non-combusted
alternatives - Two strategies for reducing smoking and improving public health.
Preventive Medicine.
Sofuoglu, M., Mitchell, E., & Mooney, M. (2009). Progesterone effects on subjective and
physiological responses to intravenous nicotine in male and female smokers. Human
Psychopharmacology: Clinical and Experimental, 24(7), 559-564.
Soneji, S., Barrington-Trimis, J. L., Wills, T. A., Leventhal, A. M., Unger, J. B., Gibson, L. A., .
. . Miech, R. A. (2017). Association Between Initial Use of e-Cigarettes and Subsequent
Cigarette Smoking Among Adolescents and Young Adults: A Systematic Review and
Meta-analysis. JAMA pediatrics.
Soneji, S., Sung, H. Y., Primack, B. A., Pierce, J. P., & Sargent, J. D. (2018). Quantifying
population-level health benefits and harms of e-cigarette use in the United States. PLoS
One, 13(3), e0193328. doi:10.1371/journal.pone.0193328
Song, M. K., Lin, F. C., Ward, S. E., & Fine, J. P. (2013). Composite variables: when and how.
Nursing Research, 62(1), 45-49. doi:10.1097/NNR.0b013e3182741948
Soule, E. K., Rosas, S. R., & Nasim, A. (2016). Reasons for electronic cigarette use beyond
cigarette smoking cessation: A concept mapping approach. Addictive behaviors, 56, 41-
50.
124
Stead, L. F., Perera, R., Bullen, C., Mant, D., & Lancaster, T. (2008). Nicotine replacement
therapy for smoking cessation. Cochrane Database Syst Rev, 1(1).
Stephens, W. E. (2017). Comparing the cancer potencies of emissions from vapourised nicotine
products including e-cigarettes with those of tobacco smoke. Tobacco control,
tobaccocontrol-2017-053808.
Tackett, A. P., Lechner, W. V., Meier, E., Grant, D. M., Driskill, L. M., Tahirkheli, N. N., &
Wagener, T. L. (2015). Biochemically verified smoking cessation and vaping beliefs
among vape store customers. Addiction, 110(5), 868-874.
Tierney, P. A., Karpinski, C. D., Brown, J. E., Luo, W., & Pankow, J. F. (2015). Flavour
chemicals in electronic cigarette fluids. Tobacco control, tobaccocontrol-2014-052175.
Tiffany, S. T., & Drobes, D. J. (1991). The development and initial validation of a questionnaire
on smoking urges. British journal of addiction, 86(11), 1467-1476.
Tobacco, T. C. P. G. T. (2008). A clinical practice guideline for treating tobacco use and
dependence: 2008 update: a US public health service report. American journal of
preventive medicine, 35(2), 158-176.
Touzani, K., Bodnar, R. J., & Sclafani, A. (2010). Neuropharmacology of learned flavor
preferences. Pharmacology Biochemistry and Behavior, 97(1), 55-62.
doi:10.1016/j.pbb.2010.06.001
Tsai, J. (2018). Reasons for Electronic Cigarette Use Among Middle and High School
Students—National Youth Tobacco Survey, United States, 2016. MMWR. Morbidity and
mortality weekly report, 67.
Tseng, T.-Y., Ostroff, J. S., Campo, A., Gerard, M., Kirchner, T., Rotrosen, J., & Shelley, D.
(2016). A randomized trial comparing the effect of nicotine versus placebo electronic
cigarettes on smoking reduction among young adult smokers. Nicotine & Tobacco
Research, ntw017.
Van Heel, M., Van Gucht, D., Vanbrabant, K., & Baeyens, F. (2017). The Importance of
Conditioned Stimuli in Cigarette and E-Cigarette Craving Reduction by E-Cigarettes.
International journal of environmental research and public health, 14(2), 193.
Villanti, A. C., Johnson, A. L., Ambrose, B. K., Cummings, K. M., Stanton, C. A., Rose, S. W., .
. . Pearson, J. L. (2017). Flavored Tobacco Product Use in Youth and Adults: Findings
From the First Wave of the PATH Study (2013–2014). American journal of preventive
medicine.
Wagener, T. L., Floyd, E. L., Stepanov, I., Driskill, L. M., Frank, S. G., Meier, E., . . .
Queimado, L. (2017). Have combustible cigarettes met their match? The nicotine
delivery profiles and harmful constituent exposures of second-generation and third-
generation electronic cigarette users. Tobacco control, 26(e1), e23-e28.
Walele, T., Sharma, G., Savioz, R., Martin, C., & Williams, J. (2016). A randomised, crossover
study on an electronic vapour product, a nicotine inhalator and a conventional cigarette.
Part B: Safety and subjective effects. Regulatory Toxicology and Pharmacology, 74, 193-
199.
Waters, A. J., Shiffman, S., Sayette, M. A., Paty, J. A., Gwaltney, C. J., & Balabanis, M. H.
(2003). Attentional bias predicts outcome in smoking cessation. Health psychology,
22(4), 378.
Watson, D., Clark, L. A., & Tellegen, A. (1988). Development and validation of brief measures
of positive and negative affect: the PANAS scales. Journal of Personality and Social
Psychology, 54(6), 1063.
125
Wayne, G. F., & Connolly, G. (2002). How cigarette design can affect youth initiation into
smoking: Camel cigarettes 1983-93. Tobacco control, 11(suppl 1), i32-i39.
Welsch, S. K., Smith, S. S., Wetter, D. W., Jorenby, D. E., Fiore, M. C., & Baker, T. B. (1999).
Development and validation of the Wisconsin Smoking Withdrawal Scale. Experimental
and clinical psychopharmacology, 7(4), 354.
West, R. (2006). Understanding nicotine and tobacco addiction.
Wetter, D. W., Kenford, S. L., Smith, S. S., Fiore, M. C., Jorenby, D. E., & Baker, T. B. (1999).
Gender differences in smoking cessation. Journal of consulting and clinical psychology,
67(4), 555.
Wickham, R. J., Nunes, E. J., Hughley, S., Silva, P., Walton, S. N., Park, J., & Addy, N. A.
(2017). Evaluating oral flavorant effects on nicotine self-administration behavior and
phasic dopamine signaling. Neuropharmacology, 128, 33-42.
doi:10.1016/j.neuropharm.2017.09.029
Wills, T. A. (2017). E-Cigarettes and Adolescents’ Risk Status. Pediatrics, e20163736.
Wills, T. A., Knight, R., Sargent, J. D., Gibbons, F. X., Pagano, I., & Williams, R. J. (2016a).
Longitudinal study of e-cigarette use and onset of cigarette smoking among high school
students in Hawaii. Tobacco control, tobaccocontrol-2015-052705.
Wills, T. A., Knight, R., Williams, R. J., Pagano, I., & Sargent, J. D. (2015). Risk factors for
exclusive e-cigarette use and dual e-cigarette use and tobacco use in adolescents.
Pediatrics, 135(1), e43-e51.
Wills, T. A., Sargent, J. D., Gibbons, F. X., Pagano, I., & Schweitzer, R. (2016b). E-cigarette use
is differentially related to smoking onset among lower risk adolescents. Tobacco control,
tobaccocontrol-2016-053116.
Yang, Y. T. (2018). FDA's regulatory shift on tobacco control. Preventive Medicine.
Yingst, J. M., Foulds, J., Veldheer, S., & Du, P. (2018). Device characteristics of long term
electronic cigarette users: A follow-up study. Addictive Behaviors.
Yingst, J. M., Veldheer, S., Hammett, E., Hrabovsky, S., & Foulds, J. (2017). A method for
classifying user-reported electronic cigarette liquid flavors. Nicotine & Tobacco
Research, ntw383.
Yip, H., & Talbot, P. (2013). Mining data on usage of electronic nicotine delivery systems
(ENDS) from YouTube videos. Tobacco control, 22(2), 103-106.
Zare, S., Nemati, M., & Zheng, Y. (2018). A systematic review of consumer preference for e-
cigarette attributes: Flavor, nicotine strength, and type. PLOS ONE, 13(3), e0194145.
doi:10.1371/journal.pone.0194145
Zhu, S.-H., Sun, J. Y., Bonnevie, E., Cummins, S. E., Gamst, A., Yin, L., & Lee, M. (2014).
Four hundred and sixty brands of e-cigarettes and counting: implications for product
regulation. Tobacco control, 23(suppl 3), iii3-iii9.

Abstract (if available)

Abstract The prevalence of electronic cigarette (e-cigarette) use (vaping) has increased among U.S. youth and adults in recent years. There is concern that e-cigarettes are adversely affecting the health of youth, as they deliver nicotine and other potentially harmful chemicals, and may contribute to the initiation of combustible tobacco product use. However, since e-cigarettes do not involve the combustion of tobacco, and contain fewer toxicants and carcinogens than combustible cigarettes, they may also be a lower risk substitute and putative harm reduction measure for adult combustible cigarette smokers. Unlike combustible cigarettes, e-cigarettes are available in a wide variety of flavorings that are extremely popular among youth as well as a portion of current and former adult smokers who vape. Flavored e-cigarettes pose a regulatory challenge, as they could both harm and possibly benefit population health. Understanding the public health impact of flavored e-cigarettes requires considering vulnerable subpopulations, such as female vapers and smokers, who may be more sensitive than males to flavored tobacco products but also have greater difficulty quitting smoking. This dissertation contributes novel evidence that can inform the current public health and regulatory debates regarding flavored e-cigarettes by examining: (1) whether use of sweet-flavored e-cigarettes is associated with subsequent (i.e., continued) vaping among adolescents

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Asset Metadata

Creator Goldenson, Nicholas Isaac (author)

Core Title Effects of flavorings in electronic cigarettes on the use and appeal of e-cigarettes among youth and adults

School Keck School of Medicine

Degree Doctor of Philosophy

Degree Program Preventive Medicine (Health Behavior Research)

Publication Date 02/04/2019

Defense Date 07/11/2018

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag adults,appeal,e-cigarette,electronic cigarette,flavor,flavored,OAI-PMH Harvest,Youth

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Leventhal, Adam (committee chair), Barrington-Trimis, Jessica (committee member), Kirkpatrick, Matthew (committee member), McConnell, Rob (committee member), Monterosso, John (committee member)

Creator Email ngoldens@usc.edu,nickgoldenson@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c89-116899

Unique identifier UC11676677

Identifier etd-GoldensonN-7041.pdf (filename),usctheses-c89-116899 (legacy record id)

Legacy Identifier etd-GoldensonN-7041.pdf

Dmrecord 116899

Document Type Dissertation

Format application/pdf (imt)

Rights Goldenson, Nicholas Isaac

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA